Compounds and compositions as selective estrogen receptor degraders

ABSTRACT

The present invention relates to compounds of formula I: 
     
       
         
         
             
             
         
       
         
         
           
             in which n, m, X, Y 1 , R 1 , R 2 , R 3 , R 4  and R 5  are defined in the Summary of the Invention; capable of being both potent antagonists and degraders of estrogen receptors. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with aberrant estrogen receptor activity.

BACKGROUND

1. Field of the Invention

The present invention relates to compounds and compositions that arepotent antagonists of estrogen receptor signaling and selective estrogenreceptor degraders (SERDs). The invention further provides a process forthe preparation of compounds of the invention, pharmaceuticalpreparations comprising such compounds and methods of using suchcompounds and compositions in the management of diseases or disordersassociated with aberrant estrogen receptor activity.

2. Background of the Invention

Estrogens play a critical role in the development of female and malereproductive tissues and contribute to the development and progressionof estrogen receptor diseases or disorders such as breast, ovarian,colon, prostate, endometrial and uterine cancers. Estrogen receptor(ERα)-positive diseases such as breast cancer are usually treated with aselective estrogen receptor modulator (SERM) or an aromatase inhibitor(AI). While these therapies have proven effective at reducing theincidence of progression of breast cancer, some patients exhibittreatment resistance and progress to advanced metastatic breast cancer.

Treatment resistance results, in part, from the evolution of tumors to astate of hypersensitivity to low estrogen levels (AI treatment) ordevelopment of dependence upon the antiestrogen for activation oftranscription (SERM treatment). SERDs degrade the receptor, effectivelyeliminating ERα expression and in so doing circumvent the underlyingmechanisms of resistance that develop to antiendocrine monotherapy.Further, clinical and preclinical data show that a significant number ofthe resistance pathways can be circumvented by the use of anantiestrogen that exhibits SERD activity.

The compounds of the present invention, as SERDs, can be used astherapies for the treatment of estrogen receptor diseases or disorders,for example, ovulatory dysfunction, uterine cancer, endometrium cancer,ovarian cancer, endometriosis, osteoporosis, prostate cancer, benignprostatic hypertrophy, estrogen receptor (ERα)-positive breast cancer,in particular ERα-positive breast cancer exhibiting denovo resistance toexisting antiestrogens and aromatase inhibitors.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of Formula I:

in which:

n is selected from 0, 1 and 2;

m is selected from 0, 1 and 2;

X is selected from O and NR₆; wherein R₆ is C₁₋₄alkyl;

Y₁ is selected from N and CR₇; wherein R₇ is selected from hydrogen andC₁₋₄alkyl;

R₁ is hydrogen;

R₂ is selected from hydrogen and halo;

R₃ is selected from —CH₂CH₂R_(8b) and —CR_(8a)═CR_(8a)R_(8b); whereineach R_(8a) is independently selected from hydrogen, fluoro andC₁₋₄alkyl; and R_(8b) is selected from —C(O)OR_(9a), —C(O)NR_(9a)R_(9b),—C(O)NHOR_(9a), —C(O)X₂R_(9a) and a 5-6 member heteroaryl selected from:

wherein the dotted line indicates the point of attachment with —CH₂CH₂or —CR_(8a)═CR_(8a) of R₃; wherein X₂ is C₁₋₄alkylene; R_(9a) and R_(9b)are independently selected from hydrogen, C₁₋₄alkyl,hydroxy-substituted-C₁₋₄alkyl and halo-substituted-C₁₋₄alkyl; whereinsaid heteroaryl of R_(8b) is unsubstituted or substituted with a groupselected from C₁₋₄alkyl and C₃₋₈cycloalkyl;

R₄ is selected from hydrogen, C₁₋₄alkyl, halo and C₁₋₃alkoxy;

R₅ is selected from C₆₋₁₀aryl and a 5-6 member heteroaryl selected from:

wherein the dotted line indicates the point of attachment with thebenzothiophene core; wherein said C₆₋₁₀aryl or heteroaryl of R₅ issubstituted where chemically available (including substitution on thenitrogen of, for example pyrazolyl) with 1 to 3 R_(5a) groupsindependently selected from hydroxy, amino, C₁₋₄alkyl, halo, nitro,cyano, halo-substituted-C₁₋₄alkyl, cyano-substituted-C₁₋₄alkyl,hydroxy-substituted-C₁₋₄alkyl, halo-substituted-C₁₋₄alkoxy, C₁₋₄alkoxy,—SF₅, —NR_(11a)R_(11b), —C(O)R_(11a) and a 4-7 member saturated ringcontaining one other heteroatom or group selected from O, NH, andS(O)₀₋₂; wherein R_(11a) and R_(11b) are independently selected fromhydrogen and C₁₋₄alkyl; or R_(11a) and R_(11b) together with thenitrogen to which they are both attached form a 4 to 7 member saturatedring containing one other heteroatom or group selected from O, NH, andS(O)₀₋₂; wherein said 4-7 member ring of R_(5a) can be unsubstituted orfurther substituted with C₁₋₄alkyl;

In a second aspect, the present invention provides a pharmaceuticalcomposition which contains a compound of Formula I or a N-oxidederivative, tautomer, individual isomers and mixture of isomers thereof;or a pharmaceutically acceptable salt thereof, in admixture with one ormore suitable excipients.

In a third aspect, the present invention provides a method of treating adisease in an animal in which a combined selective estrogen receptorantagonist and estrogen receptor degarder can prevent, inhibit orameliorate the pathology and/or symptomology of the diseases, whichmethod comprises administering to the animal a therapeutically effectiveamount of a compound of Formula I or a N-oxide derivative, individualisomers and mixture of isomers thereof, or a pharmaceutically acceptablesalt thereof.

In a fourth aspect, the present invention provides the use of a compoundof Formula I in the manufacture of a medicament for treating a diseasein an animal in which estrogen receptor activity contributes to thepathology and/or symptomology of the disease.

In a fifth aspect, the present invention provides a process forpreparing compounds of Formula I and the N-oxide derivatives, prodrugderivatives, protected derivatives, individual isomers and mixture ofisomers thereof, and the pharmaceutically acceptable salts thereof.

DEFINITIONS

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated, where more general terms whereever used may,independently of each other, be replaced by more specific definitions orremain, thus defining more detailed embodiments of the invention:

“Alkyl” refers to a fully saturated branched or unbranched hydrocarbonmoiety having up to 20 carbon atoms. Unless otherwise provided, alkylrefers to hydrocarbon moieties having 1 to 7 carbon atoms (C₁₋₇alkyl),or 1 to 4 carbon atoms (C₁₋₄alkyl). Representative examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Asubstituted alkyl is an alkyl group containing one or more, such as one,two or three substituents selected from halogen, hydroxy or alkoxygroups. Halo-substituted-alkyl and halo-substituted-alkoxy, can beeither straight-chained or branched and includes, methoxy, ethoxy,difluoromethyl, trifluoromethyl, pentafluoroethyl, difluoromethoxy,trifluoromethoxy, and the like.

“Aryl” means a monocyclic or fused bicyclic aromatic ring assemblycontaining six to ten ring carbon atoms. For example, aryl may be phenylor naphthyl, preferably phenyl. “Arylene” means a divalent radicalderived from an aryl group.

“Heteroaryl” is as defined for aryl above where one or more of the ringmembers is a heteroatom. For example C₅₋₁₀heteroaryl is a minimum of 5members as indicated by the carbon atoms but that these carbon atoms canbe replaced by a heteroatom. Consequently, C₅₋₁₀heteroaryl includespyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl,benzopyranyl, benzothiopyranyl, benzo[1,3]dioxole, imidazolyl,benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl, pyrazolyl, thienyl, etc.

“Cycloalkyl” means a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing the numberof ring atoms indicated. For example, C₃₋₁₀cycloalkyl includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

“Heterocycloalkyl” means cycloalkyl, as defined in this application,provided that one or more of the ring carbons indicated, are replaced bya moiety selected from —O—, —N═, —NR—, —C(O)—, —S—, —S(O)— or —S(O)₂—,wherein R is hydrogen, C₁₋₄alkyl or a nitrogen protecting group. Forexample, C₃₋₈heterocycloalkyl as used in this application to describecompounds of the invention includes morpholino, pyrrolidinyl,pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone,1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, thiomorpholino, sulfanomorpholino,sulfonomorpholino, etc.

“Halogen” (or halo) preferably represents chloro or fluoro, but may alsobe bromo or iodo.

Compounds of formula I may have different isomeric forms. For example,any asymmetric carbon atom may be present in the (R)-, (S)- or(R,S)-configuration, preferably in the (R)- or (S)-configuration.Substituents at a double bond or especially a ring may be present incis-(=Z-) or trans (=E-) form. The compounds may thus be present asmixtures of isomers or preferably as pure isomers, preferably as purediastereomers or pure enantiomers.

Compounds of formula I have X defined as being selected from O and NR₆;wherein R₆ is C₁₋₄alkyl. It is known that other groups such as a bond orcarbonyl at the X position is detrimental to the antagonist activity(IC₅₀ MCF7 μM) and degradation potential (ER percentage remaining) ofthe compounds. Compare the following:

                                Structure

     

 

IC₅₀ 0.748 >10 >10 MCF7 μM ER 41 76 60 Percentage remaining

Compounds of formula I have R₃ defined as being selected from—CH₂CH₂R_(8b) and —CR_(8a)═CR_(8a)R_(8b). It is known that, for examplewhere each R_(8a) and R_(8b) is hydrogen, a shorter or longer bond orderbetween the phenyl and —C(O)OH is detrimental to the antagonist activity(IC₅₀ MCF7 μM) and degradation potential (ER percentage remaining) ofthe compounds. Compare the following:

                                Structure

       

 

SERD IC₅₀ 0.748 10 10 MCF7 μM ER 41 57 55 Percentage remaining

Where the plural form (e.g. compounds, salts) is used, this includes thesingular (e.g. a single compound, a single salt). “A compound” does notexclude that (e.g. in a pharmaceutical formulation) more than onecompound of the formula I (or a salt thereof) is present, the “a” merelyrepresenting the indefinite article. “A” can thus preferably be read as“one or more”, less preferably alternatively as “one”.

Wherever a compound or compounds of the formula I are mentioned, this isfurther also intended to include N-oxides of such compounds and/ortautomers thereof.

The term “and/or an N-oxide thereof, a tautomer thereof and/or a(preferably pharmaceutically acceptable) salt thereof” especially meansthat a compound of the formula I may be present as such or in mixturewith its N-oxide, as tautomer (e.g. due to keto-enol, lactam-lactim,amide-imidic acid or enamine-imine tautomerism) or in (e.g. equivalencyreaction caused) mixture with its tautomer, or as a salt of the compoundof the formula I and/or any of these forms or mixtures of two or more ofsuch forms.

The present invention also includes all suitable isotopic variations ofthe compounds of the invention, or pharmaceutically acceptable saltsthereof. An isotopic variation of a compound of the invention or apharmaceutically acceptable salt thereof is defined as one in which atleast one atom is replaced by an atom having the same atomic number butan atomic mass different from the atomic mass usually found in nature.Examples of isotopes that may be incorporated into the compounds of theinvention and pharmaceutically acceptable salts thereof include, but arenot limited to, isotopes of hydrogen, carbon, nitrogen and oxygen suchas as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³⁵S, ¹⁸F, ³⁶Cl and ¹²³I.Certain isotopic variations of the compounds of the invention andpharmaceutically acceptable salts thereof, for example, those in which aradioactive isotope such as ³H or ¹⁴C is incorporated, are useful indrug and/or substrate tissue distribution studies. In particularexamples, ³H and ¹⁴C isotopes may be used for their ease of preparationand detectability. In other examples, substitution with isotopes such as²H may afford certain therapeutic advantages resulting from greatermetabolic stability, such as increased in vivo half-life or reduceddosage requirements. Isotopic variations of the compounds of theinvention or pharmaceutically acceptable salts thereof can generally beprepared by conventional procedures using appropriate isotopicvariations of suitable reagents. For example, compounds of the inventioncan exist in a deuterated form as shown below:

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention relates to selective estrogen receptor degraders.In one embodiment, with respect to compounds of Formula I, are compoundsof Formula Ia:

in which: n is selected from 0, 1 and 2; m is selected from 0, 1 and 2;Y₁ is selected from N and CR₇; wherein R₇ is selected from hydrogen andC₁₋₄alkyl; R₁ is hydrogen; R₂ is selected from hydrogen and halo; R₃ isselected from —CH₂CH₂R_(8b) and —CR_(8a)═CR_(8a)R_(8b);

wherein each R_(8a) is independently selected from hydrogen andC₁₋₄alkyl; and R_(8b) is selected from —C(O)OR_(9a), —C(O)NR_(9a)R_(9b),—C(O)NHOR_(9a), —C(O)X₂R_(9a), tetrazolyl, 1,3,4-oxadiazolyl,4H-1,2,4-triazolyl, 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl,2-oxo-pyrimidinyl and imidazolyl; wherein X₂ is C₁₋₄alkylene; R_(9a) andR_(9b) are independently selected from hydrogen, C₁₋₄alkyl,hydroxy-substituted-C₁₋₄alkyl and halo-substituted-C₁₋₄alkyl; whereinsaid tetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl,2-oxo-pyrimidinyl or imidazolyl of R_(8b) is unsubstituted orsubstituted with a group selected from C₁₋₄alkyl and C₃₋₈cycloalkyl; R₄is selected from hydrogen and C₁₋₄alkyl; and each R_(5a) isindependently selected from hydroxy, C₁₋₄alkyl, halo, nitro, cyano,halo-substituted-C₁₋₄alkyl, halo-substituted-C₁₋₄alkoxy,hydroxy-substituted-C₁₋₄alkyl, C₁₋₄alkoxy and —C(O)R₁₁; wherein R₁₁ isselected from hydrogen and C₁₋₄alkyl; or a pharmaceutically acceptablesalt thereof.

In a further embodiment, R₃ is selected from —CH₂CH₂R_(8b) and—CR_(8a)═CR_(8a)R_(8b); wherein each R_(8a) is independently selectedfrom hydrogen and C₁₋₄alkyl; and R_(8b) is selected from —C(O)OR_(9a),—C(O)NR_(9a)R_(9b), —C(O)NHOR_(9a) and —C(O)X₂R_(9a); wherein X₂ isC₁₋₄alkylene; R_(9a) and R_(9b) are independently selected fromhydrogen, C₁₋₄alkyl, hydroxy-substituted-C₁₋₄alkyl andhalo-substituted-C₁₋₄alkyl.

In a further embodiment, R₃ is selected from —CH₂CH₂R_(8b) and—CR_(8a)═CR_(8a)R_(8b); wherein each R_(8a) is independently selectedfrom hydrogen and C₁₋₄alkyl; and R_(8b) is selected from —C(O)OH.

In a further embodiment are compounds, or a pharmaceutically acceptablesalt thereof, selected from:

In a further embodiment is a compound, or the pharmaceuticallyacceptable salt thereof, selected from:

In another embodiment, R₃ is selected from —CH₂CH₂R_(8b) and—CR_(8a)═CR_(8a)R_(8b); wherein each R_(8a) is independently selectedfrom hydrogen and C₁₋₄alkyl; and R_(8b) is selected from tetrazolyl,1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl,5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2-oxo-pyrimidinyl andimidazolyl; wherein said tetrazolyl, 1,3,4-oxadiazolyl,4H-1,2,4-triazolyl, 2-oxo-pyrimidinyl or imidazolyl of R_(8b) isunsubstituted or substituted with a group selected from C₁₋₄alkyl andC₃₋₈cycloalkyl;

In a further embodiment, is a compound, or the pharmaceuticallyacceptable salt thereof, selected from:

In another embodiment are compounds of formula Ib:

in which: n is selected from 0, 1 and 2; m is selected from 0, 1 and 2;Y₁ is selected from N and CR₇; wherein R₇ is selected from hydrogen andC₁₋₄alkyl; R₁ is hydrogen; R₂ is selected from hydrogen and halo; R₃ isselected from —CH₂CH₂R_(8b) and —CR_(8a)═CR_(8a)R_(8b); wherein eachR_(8a) is independently selected from hydrogen and C₁₋₄alkyl; and R_(8b)is selected from —C(O)OR_(9a), —C(O)NR_(9a)R_(9b), —C(O)NHOR_(9a),—C(O)X₂R_(9a), tetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl,5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2-oxo-pyrimidinyl andimidazolyl; wherein X₂ is C₁₋₄alkylene; R_(9a) and R_(9b) areindependently selected from hydrogen, C₁₋₄alkyl,hydroxy-substituted-C₁₋₄alkyl and halo-substituted-C₁₋₄alkyl; whereinsaid tetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl,2-oxo-pyrimidinyl or imidazolyl of R_(sb) is unsubstituted orsubstituted with a group selected from C₁₋₄alkyl and C₃₋₈cycloalkyl; R₄is selected from hydrogen and C₁₋₄alkyl; each R_(5a) is independentlyselected from hydroxy, C₁₋₄alkyl, halo, nitro, cyano,halo-substituted-C₁₋₄alkyl, halo-substituted-C₁₋₄alkoxy,hydroxy-substituted-C₁₋₄alkyl, C₁₋₄alkoxy and —C(O)R₁₁; wherein R₁₁ isselected from hydrogen and C₁₋₄alkyl; and R₆ is C₁₋₄alkyl; or apharmaceutically acceptable salt thereof.

In a further embodiment, R₃ is selected from —CH₂CH₂R_(8b) and—CR_(8a)═CR_(8a)R_(8b); wherein each R_(8a) is independently selectedfrom hydrogen and C₁₋₄alkyl; and R_(8b) is selected from —C(O)OR_(9a),—C(O)NR_(9a)R_(9b), —C(O)NHOR_(9a) and —C(O)X₂R_(9a); wherein X₂ isC₁₋₄alkylene; R_(9a) and R_(9b) are independently selected fromhydrogen, C₁₋₄alkyl, hydroxy-substituted-C₁₋₄alkyl andhalo-substituted-C₁₋₄alkyl.

In a further embodiment is a compound, or a pharmaceutically acceptablesalt thereof, selected from:

Pharmacology and Utility

The present invention relates to compounds of Formula I that diminishthe effects of estrogen receptors and lower the concentrations ofestrogen receptors, and therefore, are useful as agents for thetreatment or prevention of diseases or conditions in which the actionsof estrogens or estrogen receptors are involved in the etiology orpathology of the disease or condition or contribute to at least onesymptom of the disease or condition and wherein such actions ofestrogens or estrogen receptors are undesirable. Compounds of theinvention are both potent estrogen receptor antagonists and selectiveestrogen receptor degraders (SERDS).

The estrogen receptor (ER) is a ligand-activated transcription factorthat belongs to the nuclear hormone receptor superfamily. In bothfemales and males, estrogens play an important role in the regulation ofa number of physiological processes. In humans, two different ERsubtypes are known: ERα and ERβ. Each subtype has a distinct tissuedistribution and with different biological roles. For example, ERα hashigh presence in endometrium, breast cancer cells, ovarian stroma cellsand in the hypothalamus. The expression of the ERβ protein has beendocumented in kidney, brain, bone, heart, lungs, intestinal mucosa,prostate, bladder, ovary, testis, and endothelial cells.

Pharmaceuticals such as tamoxifen, raloxifene and lasofoxifene are wellknown estrogen receptor modulators. Tamoxifen, for example, behaves likean estrogen in bone and endometrium, whereas it behaves like ananti-estrogen in breast tissue. Breast cancer is the predominantneoplastic disease in women. ERα is a major driver of breast cancerprogression. Multiple existing treatment approaches aim to reduceestrogen levels or block its binding to ERα thereby minimizing tumorprogression or even inducing tumor regression in ERα-positive breastcancer. Tamoxifen is a first-generation treatment for ERα-positivebreast cancer. However, efficacy in breast cancer treatment is seriouslycompromised by intrinsic or newly developed resistance to anti-hormonaltherapy such as treatment with tamoxifen or aromatase inhibitors. Suchresistance can exist or develop as a result of ERα phoshorylation orregulation of key components in hormone receptor and/or growth factorsignal transduction pathways. Tamoxifen resistance is driven by theresidual agonist activity of tamoxifen. Second generation treatmentssuch as toremifene, droloxifene, idoxifene, arzoxifene, and raloxifenehave failed to improve upon the efficacy of tamoxifen in the treatmentof ERα-positive breast cancer and/or demonstrated cross-resistance witheach other.

Fulvestrant is a pure ERα antagonist without the partial agonistactivity which is typical for the estrogen receptor modulators. It isthe only marketed selective estrogen receptor degrader (SERD) and it isefficacious in second-line treatment of breast cancer. Fulvestrant bothantagonizes estrogen receptors and effectively degrades ordown-regulates ERα protein levels in cells. This SERD activity inhibitsERα-driven proliferation and tumor growth. Fulvestrant, whenadministered once a month at 250 mg is equally effective to tamoxifen intreatment of ERα-positive advanced breast cancer. In second-linetreatment of ERα-positive tamoxifen-resistant breast cancer,fulvestrant, when administered once a month at 250 mg, is equallyeffective to aromatase inhibitors, despite relatively poorbioavailability and/or target exposure which limits its clinicalefficacy. A number of other SERDs exist, for example: “ICI 164,384”, astructural analog of fulvestrant; “GW5638”, a structural analog oftamoxifen; and “GW7604”, a structural analogue of 4-hydroxy-tamoxifen.

Hence, there is a need for new, potent ERα antagonists, which wouldpreferably have ER degrading or down-regulating activity in, forexample, breast cancer cells without stimulating proliferation inERα-positive, hormone treatment-resistant breast cancer cells. Suchcompounds would be orally administrable and be useful in the treatmentof, amongst other things, ERα-positive, hormone treatment-resistantbreast cancer.

Estrogen receptor-related diseases or conditions include, but are notlimited to, aberrant estrogen receptor activity associated with: cancer,for example, bone cancer, breast cancer, colorectal cancer, endometrialcancer, prostate cancer, ovarian and uterine cancer; leiomyoma, forexample, uterine leiomyoma; central nervous system defects, for example,alcoholism and migraine; cardiovascular system defects, for example,aortic aneurysm, susceptibility to myocardial infarction, aortic valvesclerosis, cardiovascular disease, coronary artery disease andhypertension; hematological system defects, for example, deep veinthrombosis; immune and inflammation diseases, for example, Graves'Disease, arthritis, mulitple sclerosis and cirrhosis; susceptibility toinfection, for example, hepatitis B and chronic liver disease; metabolicdefects, for example, bone density, cholestasis, hypospadias, obesity,osteoarthritis, osteopenia and osteoporosis; neurological defects, forexample, Alzheimer's disease, Parkinson's disease, migraine and vertigo;psychiatric defects, for example, anorexia nervosa, attention deficityhyperactivity disorder, dementia, major depressive disorder andpsychosis; and reproductive defects, for example, age of menarche,endometriosis and infertility. In the context of treating cancers, thecompound of Formula I offer improved therapeutic activity characterizedby complete or longer-lasting tumor regression, a lower incidence orrate of development of resistance to treatment, and/or a reduction intumor invasiveness.

The present invention relates to compounds that are both potent estrogenreceptor antagonists and selective estrogen receptor degraders. Theinvention further provides a process for the preparation of compounds ofthe invention and pharmaceutical preparations comprising such compounds.Another aspect of the present invention relates to a method of treatingdisorders mediated by estrogen receptors comprising the step ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound of formula I as defined in the

SUMMARY OF THE INVENTION

In an embodiment, compounds of the invention are used to treat cancer ina mammal.

In a further embodiment, the cancer is selected from breast, ovarian,endometrial, prostate, uterine, cervical and lung cancers.

In a further embodiment, the cancer is breast cancer.

In another embodiment, the cancer is a hormone dependent cancer.

In another embodiment, the cancer is an estrogen receptor dependentcancer.

In a further embodiment, the cancer is an estrogen-sensitive cancer.

In another embodiment, the cancer is resistant to anti-hormonaltreatment.

In a further embodiment, the cancer is an estrogen-sensitive cancer oran estrogen receptor dependent cancer that is resistant to anti-hormonaltreatment.

In a further embodiment, the anti-hormonal treatment includes treatmentwith at least one agent selected from tamoxifen, fulvestrant, asteroidal aromatase inhibitor, and a non-steroidal aromatase inhibitor.

In another embodiment, compounds of the invention are used to treathormone receptor positive metastatic breast cancer in a postmenopausalwoman with disease progression following anti-estrogen therapy.

In another embodiment, compounds of the invention are used to treat ahormonal dependent benign or malignant disease of the breast orreproductive tract in a mammal.

In a further embodiment, the benign or malignant disease is breastcancer.

In another embodiment, compounds of the invention are used to treatcancer in a mammal, wherein the mammal is chemotherapy-naive.

In another embodiment, compounds of the invention are used to treatcancer in a mammal, wherein the mammal is being treated for cancer withat least one anti-cancer agent.

In a further embodiment, the cancer is a hormone refractory cancer.

In another embodiment, compounds of the invention are used in thetreatment of endometriosis in a mammal.

In another embodiment, compounds of the invention are used in thetreatment of leiomyoma in a mammal.

In a further embodiment, the leiomyoma is selected from uterineleiomyoma, esophageal leiomyoma, cutaneous leiomyoma and small bowelleiomyoma.

In another embodiment, compounds of the invention are used in thetreatment of fibroids, for example, uterine fibroids, in a mammal.

Compounds of the present invention may be usefully combined with anotherpharmacologically active compound, or with two or more otherpharmacologically active compounds, particularly in the treatment ofcancer. For example, a compound of the formula (I), or apharmaceutically acceptable salt thereof, as defined above, may beadministered simultaneously, sequentially or separately in combinationwith one or more agents selected from chemotherapy agents, for example,mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel,docetaxel, vincristine, vinblastine, vinorelbine or vinflunine, andother anticancer agents, e.g. cisplatin, 5-fluorouracil or5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine.

Such combinations may offer significant advantages, includingsynergistic activity, in therapy.

In certain embodiments, the present invention relates to theaforementioned method, wherein said compound is administeredparenterally.

In certain embodiments, the present invention relates to theaforementioned method, wherein said compound is administeredintramuscularly, intravenously, subcutaneously, orally, pulmonary,intrathecally, topically or intranasally.

In certain embodiments, the present invention relates to theaforementioned method, wherein said compound is administeredsystemically.

In certain embodiments, the present invention relates to theaforementioned method, wherein said patient is a mammal.

In certain embodiments, the present invention relates to theaforementioned method, wherein said patient is a primate.

In certain embodiments, the present invention relates to theaforementioned method, wherein said patient is a human.

In another aspect, the present invention relates to a method of treatinga disorder mediated by estrogen receptors, comprising the step of:administering to a patient in need thereof a therapeutically effectiveamount of a chemothereutic agent in combination with a therapeuticallyeffective amount of a compound of formula I as defined in the Summary ofthe Invention.

Pharmaceutical Compositions

In another aspect, the present invention provides pharmaceuticallyacceptable compositions which comprise a therapeutically-effectiveamount of one or more of the compounds described above, formulatedtogether with one or more pharmaceutically acceptable carriers(additives) and/or diluents. As described in detail below, thepharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) oral administration, for example,drenches (aqueous or non-aqueous solutions or suspensions), tablets,e.g., those targeted for buccal, sublingual, and systemic absorption,boluses, powders, granules, pastes for application to the tongue; (2)parenteral administration, for example, by subcutaneous, intramuscular,intravenous or epidural injection as, for example, a sterile solution orsuspension, or sustained-release formulation; (3) topical application,for example, as a cream, ointment, or a controlled-release patch orspray applied to the skin; (4) intravaginally or intrarectally, forexample, as a pessary, cream or foam; (5) sublingually; (6) ocularly;(7) transdermally; (8) nasally; (9) pulmonary; or (10) intrathecally.

The phrase “therapeutically-effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect in at least a sub-population of cells in an animal ata reasonable benefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, manufacturing aid (e.g.,lubricant, talc magnesium, calcium or zinc stearate, or steric acid), orsolvent encapsulating material, involved in carrying or transporting thesubject compound from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically-acceptable carriers include: (1) sugars, suchas lactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

As set out above, certain embodiments of the present compounds maycontain a basic functional group, such as amino or alkylamino, and are,thus, capable of forming pharmaceutically-acceptable salts withpharmaceutically-acceptable acids. The term “pharmaceutically-acceptablesalts” in this respect, refers to the relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ in the administration vehicle or thedosage form manufacturing process, or by separately reacting a purifiedcompound of the invention in its free base form with a suitable organicor inorganic acid, and isolating the salt thus formed during subsequentpurification. Representative salts include the hydrobromide,hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,valerate, oleate, palmitate, stearate, laurate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonatesalts and the like. (See, for example, Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

The pharmaceutically acceptable salts of the subject compounds includethe conventional nontoxic salts or quaternary ammonium salts of thecompounds, e.g., from non-toxic organic or inorganic acids. For example,such conventional nontoxic salts include those derived from inorganicacids such as hydrochloride, hydrobromic, sulfuric, sulfamic,phosphoric, nitric, and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic, and the like.

In other cases, the compounds of the present invention may contain oneor more acidic functional groups and, thus, are capable of formingpharmaceutically-acceptable salts with pharmaceutically-acceptablebases. The term “pharmaceutically-acceptable salts” in these instancesrefers to the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present invention. These salts can likewise beprepared in situ in the administration vehicle or the dosage formmanufacturing process, or by separately reacting the purified compoundin its free acid form with a suitable base, such as the hydroxide,carbonate or bicarbonate of a pharmaceutically-acceptable metal cation,with ammonia, or with a pharmaceutically-acceptable organic primary,secondary or tertiary amine. Representative alkali or alkaline earthsalts include the lithium, sodium, potassium, calcium, magnesium, andaluminum salts and the like. Representative organic amines useful forthe formation of base addition salts include ethylamine, diethylamine,ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.(See, for example, Berge et al., supra)

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, out of one hundred percent, this amount will range from about0.1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present invention. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentinvention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-shelled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, oral, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient, when used for the indicated analgesic effects,will range from about 0.0001 to about 100 mg per kilogram of body weightper day.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. Preferred dosing is one administrationper day.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical formulation (composition).

The compounds according to the invention may be formulated foradministration in any convenient way for use in human or veterinarymedicine, by analogy with other pharmaceuticals.

In another aspect, the present invention provides pharmaceuticallyacceptable compositions which comprise a therapeutically-effectiveamount of one or more of the subject compounds, as described above,formulated together with one or more pharmaceutically acceptablecarriers (additives) and/or diluents. As described in detail below, thepharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) oral administration, for example,drenches (aqueous or non-aqueous solutions or suspensions), tablets,boluses, powders, granules, pastes for application to the tongue; (2)parenteral administration, for example, by subcutaneous, intramuscularor intravenous injection as, for example, a sterile solution orsuspension; (3) topical application, for example, as a cream, ointmentor spray applied to the skin, lungs, or mucous membranes; or (4)intravaginally or intrarectally, for example, as a pessary, cream orfoam; (5) sublingually or buccally; (6) ocularly; (7) transdermally; or(8) nasally.

The term “treatment” is intended to encompass also prophylaxis, therapyand cure.

The patient receiving this treatment is any animal in need, includingprimates, in particular humans, and other mammals such as equines,cattle, swine and sheep; and poultry and pets in general.

The compound of the invention can be administered as such or inadmixtures with pharmaceutically acceptable carriers and can also beadministered in conjunction with antimicrobial agents such aspenicillins, cephalosporins, aminoglycosides and glycopeptides.Conjunctive therapy, thus includes sequential, simultaneous and separateadministration of the active compound in a way that the therapeuticaleffects of the first administered one is not entirely disappeared whenthe subsequent is administered.

Microemulsification technology can improve bioavailability of somelipophilic (water insoluble) pharmaceutical agents. Examples includeTrimetrine (Dordunoo, S. K., et al., Drug Development and IndustrialPharmacy, 17(12), 1685-1713, 1991 and REV 5901 (Sheen, P. C., et al., JPharm Sci 80(7), 712-714, 1991). Among other things, microemulsificationprovides enhanced bioavailability by preferentially directing absorptionto the lymphatic system instead of the circulatory system, which therebybypasses the liver, and prevents destruction of the compounds in thehepatobiliary circulation.

While all suitable amphiphilic carriers are contemplated, the presentlypreferred carriers are generally those that haveGenerally-Recognized-as-Safe (GRAS) status, and that can both solubilizethe compound of the present invention and microemulsify it at a laterstage when the solution comes into a contact with a complex water phase(such as one found in human gastrointestinal tract). Usually,amphiphilic ingredients that satisfy these requirements have HLB(hydrophilic to lipophilic balance) values of 2-20, and their structurescontain straight chain aliphatic radicals in the range of C-6 to C-20.Examples are polyethylene-glycolized fatty glycerides and polyethyleneglycols.

Commercially available amphiphilic carriers are particularlycontemplated, including Gelucire-series, Labrafil, Labrasol, orLauroglycol (all manufactured and distributed by Gattefosse Corporation,Saint Priest, France), PEG-mono-oleate, PEG-di-oleate, PEG-mono-laurateand di-laurate, Lecithin, Polysorbate 80, etc (produced and distributedby a number of companies in USA and worldwide).

Hydrophilic polymers suitable for use in the present invention are thosewhich are readily water-soluble, can be covalently attached to avesicle-forming lipid, and which are tolerated in vivo without toxiceffects (i.e., are biocompatible). Suitable polymers includepolyethylene glycol (PEG), polylactic (also termed polylactide),polyglycolic acid (also termed polyglycolide), a polylactic-polyglycolicacid copolymer, and polyvinyl alcohol. Preferred polymers are thosehaving a molecular weight of from about 100 or 120 daltons up to about5,000 or 10,000 daltons, and more preferably from about 300 daltons toabout 5,000 daltons. In a particularly preferred embodiment, the polymeris polyethyleneglycol having a molecular weight of from about 100 toabout 5,000 daltons, and more preferably having a molecular weight offrom about 300 to about 5,000 daltons. In a particularly preferredembodiment, the polymer is polyethyleneglycol of 750 daltons (PEG(750)).Polymers may also be defined by the number of monomers therein; apreferred embodiment of the present invention utilizes polymers of atleast about three monomers, such PEG polymers consisting of threemonomers (approximately 150 daltons).

Other hydrophilic polymers which may be suitable for use in the presentinvention include polyvinylpyrrolidone, polymethoxazoline,polyethyloxazoline, polyhydroxypropyl methacrylamide,polymethacrylamide, polydimethylacrylamide, and derivatized cellulosessuch as hydroxymethylcellulose or hydroxyethylcellulose.

In certain embodiments, a formulation of the present invention comprisesa biocompatible polymer selected from the group consisting ofpolyamides, polycarbonates, polyalkylenes, polymers of acrylic andmethacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes,polyurethanes and co-polymers thereof, celluloses, polypropylene,polyethylenes, polystyrene, polymers of lactic acid and glycolic acid,polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid),poly(lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronicacids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.

Cyclodextrins are cyclic oligosaccharides, consisting of 6, 7 or 8glucose units, designated by the Greek letter .alpha., .beta. or.gamma., respectively. Cyclodextrins with fewer than six glucose unitsare not known to exist. The glucose units are linked byalpha-1,4-glucosidic bonds. As a consequence of the chair conformationof the sugar units, all secondary hydroxyl groups (at C-2, C-3) arelocated on one side of the ring, while all the primary hydroxyl groupsat C-6 are situated on the other side. As a result, the external facesare hydrophilic, making the cyclodextrins water-soluble. In contrast,the cavities of the cyclodextrins are hydrophobic, since they are linedby the hydrogen of atoms C-3 and C-5, and by ether-like oxygens. Thesematrices allow complexation with a variety of relatively hydrophobiccompounds, including, for instance, steroid compounds such as17.beta.-estradiol (see, e.g., van Uden et al. Plant Cell Tiss. Org.Cult. 38:1-3-113 (1994)). The complexation takes place by Van der Waalsinteractions and by hydrogen bond formation. For a general review of thechemistry of cyclodextrins, see, Wenz, Agnew. Chem. Int. Ed. Engl.,33:803-822 (1994).

The physico-chemical properties of the cyclodextrin derivatives dependstrongly on the kind and the degree of substitution. For example, theirsolubility in water ranges from insoluble (e.g.,triacetyl-beta-cyclodextrin) to 147% soluble (w/v)(G-2-beta-cyclodextrin). In addition, they are soluble in many organicsolvents. The properties of the cyclodextrins enable the control oversolubility of various formulation components by increasing or decreasingtheir solubility.

Numerous cyclodextrins and methods for their preparation have beendescribed. For example, Parmeter (I), et al. (U.S. Pat. No. 3,453,259)and Gramera, et al. (U.S. Pat. No. 3,459,731) described electroneutralcyclodextrins. Other derivatives include cyclodextrins with cationicproperties [Parmeter (II), U.S. Pat. No. 3,453,257], insolublecrosslinked cyclodextrins (Solms, U.S. Pat. No. 3,420,788), andcyclodextrins with anionic properties [Parmeter (III), U.S. Pat. No.3,426,011]. Among the cyclodextrin derivatives with anionic properties,carboxylic acids, phosphorous acids, phosphinous acids, phosphonicacids, phosphoric acids, thiophosphonic acids, thiosulphinic acids, andsulfonic acids have been appended to the parent cyclodextrin [see,Parmeter (III), supra]. Furthermore, sulfoalkyl ether cyclodextrinderivatives have been described by Stella, et al. (U.S. Pat. No.5,134,127).

Liposomes consist of at least one lipid bilayer membrane enclosing anaqueous internal compartment. Liposomes may be characterized by membranetype and by size. Small unilamellar vesicles (SUVs) have a singlemembrane and typically range between 0.02 and 0.05 μm in diameter; largeunilamellar vesicles (LUVS) are typically larger than 0.05 μmOligolamellar large vesicles and multilamellar vesicles have multiple,usually concentric, membrane layers and are typically larger than 0.1μm. Liposomes with several nonconcentric membranes, i.e., severalsmaller vesicles contained within a larger vesicle, are termedmultivesicular vesicles.

One aspect of the present invention relates to formulations comprisingliposomes containing a compound of the present invention, where theliposome membrane is formulated to provide a liposome with increasedcarrying capacity. Alternatively or in addition, the compound of thepresent invention may be contained within, or adsorbed onto, theliposome bilayer of the liposome. The compound of the present inventionmay be aggregated with a lipid surfactant and carried within theliposome's internal space; in these cases, the liposome membrane isformulated to resist the disruptive effects of the activeagent-surfactant aggregate.

According to one embodiment of the present invention, the lipid bilayerof a liposome contains lipids derivatized with polyethylene glycol(PEG), such that the PEG chains extend from the inner surface of thelipid bilayer into the interior space encapsulated by the liposome, andextend from the exterior of the lipid bilayer into the surroundingenvironment.

Active agents contained within liposomes of the present invention are insolubilized form. Aggregates of surfactant and active agent (such asemulsions or micelles containing the active agent of interest) may beentrapped within the interior space of liposomes according to thepresent invention. A surfactant acts to disperse and solubilize theactive agent, and may be selected from any suitable aliphatic,cycloaliphatic or aromatic surfactant, including but not limited tobiocompatible lysophosphatidylcholines (LPCs) of varying chain lengths(for example, from about C.sub.14 to about C.sub.20).Polymer-derivatized lipids such as PEG-lipids may also be utilized formicelle formation as they will act to inhibit micelle/membrane fusion,and as the addition of a polymer to surfactant molecules decreases theCMC of the surfactant and aids in micelle formation. Preferred aresurfactants with CMCs in the micromolar range; higher CMC surfactantsmay be utilized to prepare micelles entrapped within liposomes of thepresent invention, however, micelle surfactant monomers could affectliposome bilayer stability and would be a factor in designing a liposomeof a desired stability.

Liposomes according to the present invention may be prepared by any of avariety of techniques that are known in the art. See, e.g., U.S. Pat.No. 4,235,871; Published PCT applications WO 96/14057; New RRC,Liposomes: A practical approach, IRL Press, Oxford (1990), pages 33-104;Lasic DD, Liposomes from physics to applications, Elsevier SciencePublishers BV, Amsterdam, 1993.

For example, liposomes of the present invention may be prepared bydiffusing a lipid derivatized with a hydrophilic polymer into preformedliposomes, such as by exposing preformed liposomes to micelles composedof lipid-grafted polymers, at lipid concentrations corresponding to thefinal mole percent of derivatized lipid which is desired in theliposome. Liposomes containing a hydrophilic polymer can also be formedby homogenization, lipid-field hydration, or extrusion techniques, asare known in the art.

In one aspect of the present invention, the liposomes are prepared tohave substantially homogeneous sizes in a selected size range. Oneeffective sizing method involves extruding an aqueous suspension of theliposomes through a series of polycarbonate membranes having a selecteduniform pore size; the pore size of the membrane will correspond roughlywith the largest sizes of liposomes produced by extrusion through thatmembrane. See e.g., U.S. Pat. No. 4,737,323 (Apr. 12, 1988).

The release characteristics of a formulation of the present inventiondepend on the encapsulating material, the concentration of encapsulateddrug, and the presence of release modifiers. For example, release can bemanipulated to be pH dependent, for example, using a pH sensitivecoating that releases only at a low pH, as in the stomach, or a higherpH, as in the intestine. An enteric coating can be used to preventrelease from occurring until after passage through the stomach. Multiplecoatings or mixtures of cyanamide encapsulated in different materialscan be used to obtain an initial release in the stomach, followed bylater release in the intestine. Release can also be manipulated byinclusion of salts or pore forming agents, which can increase wateruptake or release of drug by diffusion from the capsule. Excipientswhich modify the solubility of the drug can also be used to control therelease rate. Agents which enhance degradation of the matrix or releasefrom the matrix can also be incorporated. They can be added to the drug,added as a separate phase (i.e., as particulates), or can beco-dissolved in the polymer phase depending on the compound. In allcases the amount should be between 0.1 and thirty percent (w/w polymer).Types of degradation enhancers include inorganic salts such as ammoniumsulfate and ammonium chloride, organic acids such as citric acid,benzoic acid, and ascorbic acid, inorganic bases such as sodiumcarbonate, potassium carbonate, calcium carbonate, zinc carbonate, andzinc hydroxide, and organic bases such as protamine sulfate, spermine,choline, ethanolamine, diethanolamine, and triethanolamine andsurfactants such as Tween® and Pluronic®. Pore forming agents which addmicrostructure to the matrices (i.e., water soluble compounds such asinorganic salts and sugars) are added as particulates. The range shouldbe between one and thirty percent (w/w polymer).

Uptake can also be manipulated by altering residence time of theparticles in the gut. This can be achieved, for example, by coating theparticle with, or selecting as the encapsulating material, a mucosaladhesive polymer. Examples include most polymers with free carboxylgroups, such as chitosan, celluloses, and especially polyacrylates (asused herein, polyacrylates refers to polymers including acrylate groupsand modified acrylate groups such as cyanoacrylates and methacrylates).

Pharmaceutical Combinations

The invention especially relates to the use of a compound of the formulaI (or a pharmaceutical composition comprising a compound of the formulaI) in the treatment of one or more of the diseases mentioned herein;wherein the response to treatment is beneficial as demonstrated, forexample, by the partial or complete removal of one or more of thesymptoms of the disease up to complete cure or remission.

Given the central role of ER-α in breast cancer development andprogression, compounds disclosed herein are useful in the treatment ofbreast cancer, either alone or in combination with other agents used totreat breast cancer, including but not limited to aromatase inhibitors,anthracylines, platins, nitrogen mustard alkylating agents and taxanes.Agents used to treat breast cancer, include, but are not limited to,paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin,fulvestrant, letrozole, gemcitabine, trastuzumab, pegfilgrastim,filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabineand ixabepilone.

Further, compounds of the invention are useful in the treatment ofbreast cancer, either alone or in combination with other agents thatmodulate other critical pathways in breast cancer, including but notlimited to those that target IGF1R, EGFR, erB-B2 and the PI3K/AKT/mTORaxis, Rb axis including CDK4/6 and D-cyclins, HSP90, PARP and/or histonedeacetylases.

A compound of the invention can, therefore, also be used in combinationwith the following:

Vascular Endothelial Growth Factor (VEGF) receptor inhibitors:Bevacizumab (sold under the trademark Avastin® by Genentech/Roche),axitinib,(N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide,also known as AG013736, and described in PCT Publication No. WO01/002369), Brivanib Alaninate((S)—((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)-2-aminopropanoate,also known as BMS-582664), motesanib(N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide,and described in PCT Publication No. WO 02/066470), pasireotide (alsoknown as SOM230, and described in PCT Publication No. WO 02/010192),sorafenib (sold under the tradename Nexavar®);

HER2 receptor inhibitors: Trastuzumab (sold under the trademarkHerceptin® by Genentech/Roche), neratinib (also known as HKI-272,(2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide,and described PCT Publication No. WO 05/028443), lapatinib or lapatinibditosylate (sold under the trademark Tykerb® by GlaxoSmithKline);

CD20 antibodies: Rituximab (sold under the trademarks Riuxan® andMabThera® by Genentech/Roche), tositumomab (sold under the trademarksBexxar® by GlaxoSmithKline), ofatumumab (sold under the trademarkArzerra® by GlaxoSmithKline);

Tyrosine kinase inhibitors: Erlotinib hydrochloride (sold under thetrademark Tarceva® by Genentech/Roche), Linifanib(N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea,also known as ABT 869, available from Genentech), sunitinib malate (soldunder the tradename Sutent® by Pfizer), bosutinib(4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile,also known as SKI-606, and described in U.S. Pat. No. 6,780,996),dasatinib (sold under the tradename Sprycel® by Bristol-Myers Squibb),armala (also known as pazopanib, sold under the tradename Votrient® byGlaxoSmithKline), imatinib and imatinib mesylate (sold under thetradenames Gilvec® and Gleevec® by Novartis);

Bcr/Abl kinase inhibitors: nilotinib hydrochloride (sold under thetradename Tasigna® by Novartis);

DNA Synthesis inhibitors: Capecitabine (sold under the trademark Xeloda®by Roche), gemcitabine hydrochloride (sold under the trademark Gemzar®by Eli Lilly and Company), nelarabine((2R,3S,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol,sold under the tradenames Arranon® and Atriance® by GlaxoSmithKline);

Antineoplastic agents: oxaliplatin (sold under the tradename Eloxatin®ay Sanofi-Aventis and described in U.S. Pat. No. 4,169,846);

Epidermal GROWTH FACTOR RECEPTOR (EGFR) inhibitors: Gefitnib (sold underthe tradename Iressa®),N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3“S”)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide,sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab(sold under the tradename Erbitux® by Bristol-Myers Squibb), panitumumab(sold under the tradename Vectibix® by Amgen);

HER dimerization inhibitors: Pertuzumab (sold under the trademarkOmnitarg®, by Genentech);

Human Granulocyte colony-stimulating factor (G-CSF) modulators:Filgrastim (sold under the tradename Neupogen® by Amgen);

Immunomodulators: Afutuzumab (available from Roche®), pegfilgrastim(sold under the tradename Neulasta® by Amgen), lenalidomide (also knownas CC-5013, sold under the tradename Revlimid®), thalidomide (sold underthe tradename Thalomid®);

CD40 inhibitors: Dacetuzumab (also known as SGN-40 or huS2C6, availablefrom Seattle Genetics, Inc);

Pro-apoptotic receptor agonists (PARAs): Dulanermin (also known asAMG-951, available from Amgen/Genentech);

Hedgehog antagonists:2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)-benzamide(also known as GDC-0449, and described in PCT Publication No. WO06/028958);

PI3K inhibitors:4-[2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine(also known as GDC 0941 and described in PCT Publication Nos. WO09/036,082 and WO 09/055,730),2-Methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile(also known as BEZ 235 or NVP-BEZ 235, and described in PCT PublicationNo. WO 06/122806);

Phospholipase A2 inhibitors: Anagrelide (sold under the tradenameAgrylin®);

BCL-2 inhibitors:4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide(also known as ABT-263 and described in PCT Publication No. WO09/155,386);

Mitogen-activated protein kinase kinase (MEK) inhibitors: XL-518 (CasNo. 1029872-29-4, available from ACC Corp.);

Aromatase inhibitors: Exemestane (sold under the trademark Aromasin® byPfizer), letrozole (sold under the tradename Femara® by Novartis),anastrozole (sold under the tradename Arimidex®);

Topoisomerase I inhibitors: Irinotecan (sold under the trademarkCamptosar® by Pfizer), topotecan hydrochloride (sold under the tradenameHycamtin® by GlaxoSmithKline);

Topoisomerase II inhibitors: etoposide (also known as VP-16 andEtoposide phosphate, sold under the tradenames Toposar®, VePesid® andEtopophos®), teniposide (also known as VM-26, sold under the tradenameVumon®);

mTOR inhibitors: Temsirolimus (sold under the tradename Torisel® byPfizer), ridaforolimus (formally known as deferolimus,(1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0^(4,9)]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669, and described inPCT Publication No. WO 03/064383), everolimus (sold under the tradenameAfinitor® by Novartis);

Osteoclastic bone resorption inhibitors:1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate(sold under the tradename Zometa® by Novartis);

CD33 Antibody Drug Conjugates. Gemtuzumab ozogamicin (sold under thetradename Mylotarg® by Pfizer/Wyeth);

CD22 Antibody Drug Conjugates. Inotuzumab ozogamicin (also referred toas CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co.,Ltd.);

CD20 Antibody Drug Conjugates. Ibritumomab tiuxetan (sold under thetradename Zevalin®);

Somatostain analogs: octreotide (also known as octreotide acetate, soldunder the tradenames Sandostatin® and Sandostatin LAR®);

Synthetic Interleukin-11 (IL-11): oprelvekin (sold under the tradenameNeumega® by Pfizer/Wyeth);

Synthetic erythropoietin: Darbepoetin alfa (sold under the tradenameAranesp® by Amgen);

Receptor Activator for Nuclear Factor κ B (RANK) inhibitors. Denosumab(sold under the tradename Prolia® by Amgen);

Thrombopoietin mimetic peptibodies. Romiplostim (sold under thetradename Nplate® by Amgen;

Cell growth stimulators. Palifermin (sold under the tradename Kepivance®by Amgen);

Anti-Insulin-like Growth Factor-1 receptor (IGF-IR) antibodies.Figitumumab (also known as CP-751,871, available from ACC Corp),robatumumab (CAS No. 934235-44-6);

Anti-CS1 antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3);

CD52 antibodies: Alemtuzumab (sold under the tradename Campath®);

CTLA-4 inhibitors: Tremelimumab (IgG2 monoclonal antibody available fromPfizer, formerly known as ticilimumab, CP-675,206), ipilimumab (CTLA-4antibody, also known as MDX-010, CAS No. 477202-00-9);

Histone deacetylase inhibitors (HDI). Voninostat (sold under thetradename Zolinza® by Merck);

Alkylating agents. Temozolomide (sold under the tradenames Temodar® andTemodal® by Schering-Plough/Merck), dactinomycin (also known asactinomycin-D and sold under the tradename Cosmegen®), melphalan (alsoknown as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under thetradename Alkeran®), altretamine (also known as hexamethylmelamine(HMM), sold under the tradename Hexylen®), carmustine (sold under thetradename BiCNU®), bendamustine (sold under the tradename Treanda®),busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin(sold under the tradename Paraplatin®), lomustine (also known as CCNU,sold under the tradename CeeNU®), cisplatin (also known as CDDP, soldunder the tradenames Platinol® and Platinol®-AQ), chlorambucil (soldunder the tradename Leukeran®), cyclophosphamide (sold under thetradenames Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DICand imidazole carboxamide, sold under the tradename DTIC-Dome®),altretamine (also known as hexamethylmelamine (HMM) sold under thetradename Hexylen®), ifosfamide (sold under the tradename Ifex®),procarbazine (sold under the tradename Matulane®), mechlorethamine (alsoknown as nitrogen mustard, mustine and mechloroethamine hydrochloride,sold under the tradename Mustargen®), streptozocin (sold under thetradename Zanosar®), thiotepa (also known as thiophosphoamide, TESPA andTSPA, sold under the tradename Thioplex®;

Biologic response modifiers: bacillus calmette-guerin (sold under thetradenames theraCys® and TICE® BCG), denileukin diftitox (sold under thetradename Ontak®);

Anti-tumor antibiotics: doxorubicin (sold under the tradenamesAdriamycin® and Rubex®), bleomycin (sold under the tradename Lenoxane®),daunorubicin (also known as dauorubicin hydrochloride, daunomycin, andrubidomycin hydrochloride, sold under the tradename Cerubidine®),daunorubicin liposomal (daunorubicin citrate liposome, sold under thetradename DaunoXome®), mitoxantrone (also known as DHAD, sold under thetradename Novantrone®), epirubicin (sold under the tradename Ellence™),idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®),mitomycin C (sold under the tradename Mutamycin®);

Anti-microtubule agents. Estramustine (sold under the tradename Emcyl®);

Cathepsin K inhibitors: Odanacatib (also know as MK-0822,N-(1-cyanocyclopropyl)-4-fluoro-N²-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide,available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, anddescribed in PCT Publication no. WO 03/075836);

Epothilone B analogs: Ixabepilone (sold under the tradename Lxempra® byBristol-Myers Squibb);

Heat Shock Protein (HSP) inhibitors. Tanespimycin(17-allylamino-17-demethoxygeldanamycin, also known as KOS-953 and17-AAG, available from SIGMA, and described in U.S. Pat. No. 4,261,989);

TpoR agonists: Eltrombopag (sold under the tradenames Promacta® andRevolade® by GlaxoSmithKline);

Anti-mitotic agents: Docetaxel (sold under the tradename Taxotere® bySanofi-Aventis);

Adrenal steroid inhibitors: aminoglutethimide (sold under the tradenameCytadren®);

Anti-androgens: Nilutamide (sold under the tradenames Nilandron® andAnandron®), bicalutamide (sold under tradename Casodex®), flutamide(sold under the tradename Fulexin™);

Androgens: Fluoxymesterone (sold under the tradename Halotestin®);

Proteasome inhibitors: Bortezomib (sold under the tradename Velcade®);

CDK1 inhibitors: Alvocidib (also known as flovopirdol or HMR-1275,2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone,and described in U.S. Pat. No. 5,621,002);

Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide orleuprolide acetate (sold under the tradenames Viadure® by Bayer AG,Eligard® by Sanofi-Aventis and Lupron® by Abbott Lab);

Taxane anti-neoplastic agents. Cabazitaxel(1-hydroxy-7β,10β-dimethoxy-9-oxo-5β,20-epoxytax-11-ene-2α,4,13α-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate),larotaxel((2α,3ξ,4α,5β,7α,10β,13α)-4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotax-11-en-2-ylbenzoate);

5HT1a receptor agonists: Xaliproden (also known as SR57746,1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine,and described in U.S. Pat. No. 5,266,573);

HPC vaccines: Cervarix® sold by GlaxoSmithKline, Gardasil® sold byMerck;

Iron Chelating agents: Deferasinox (sold under the tradename Exjade® byNovartis);

Anti-metabolites. Claribine (2-chlorodeoxyadenosine, sold under thetradename Leustatin®), 5-fluorouracil (sold under the tradenameAdrucil®), 6-thioguanine (sold under the tradename Purinethol®),pemetrexed (sold under the tradename Alimta®), cytarabine (also known asarabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®),cytarabine liposomal (also known as Liposomal Ara-C, sold under thetradename DepoCyt™), decitabine (sold under the tradename Dacogen®),hydroxyurea (sold under the tradenames Hydrea®, Droxia™ and Mylocel™),fludarabine (sold under the tradename Fludara®), floxuridine (sold underthe tradename FUDR®), cladribine (also known as 2-chlorodeoxyadenosine(2-CdA) sold under the tradename Leustatin™), methotrexate (also knownas amethopterin, methotrexate sodim (MTX), sold under the tradenamesRheumatrex® and Trexall™), pentostatin (sold under the tradenameNipent®);

Bisphosphonates: Pamidronate (sold under the tradename Aredia®),zoledronic acid (sold under the tradename Zometa®);

Demethylating agents: 5-azacitidine (sold under the tradename Vidaza®),decitabine (sold under the tradename Dacogen®);

Plant Alkaloids: Paclitaxel protein-bound (sold under the tradenameAbraxane®), vinblastine (also known as vinblastine sulfate,vincaleukoblastine and VLB, sold under the tradenames Alkaban-AQ® andVelban®), vincristine (also known as vincristine sulfate, LCR, and VCR,sold under the tradenames Oncovin® and Vincasar Pfs®), vinorelbine (soldunder the tradename Navelbine®), paclitaxel (sold under the tradenamesTaxol and Onxal™);

Retinoids: Alitretinoin (sold under the tradename Panretin®), tretinoin(all-trans retinoic acid, also known as ATRA, sold under the tradenameVesanoid®), Isotretinoin (13-cis-retinoic acid, sold under thetradenames Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®,Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (soldunder the tradename Targretin®);

Glucocorticosteroids: Hydrocortisone (also known as cortisone,hydrocortisone sodium succinate, hydrocortisone sodium phosphate, andsold under the tradenames Ala-Cort®, Hydrocortisone Phosphate,Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethazone((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one),prednisolone (sold under the tradenames Delta-Cortel®, Orapred®,Pediapred® and Prelone®), prednisone (sold under the tradenamesDeltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone(also known as 6-Methylprednisolone, Methylprednisolone Acetate,Methylprednisolone Sodium Succinate, sold under the tradenamesDuralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®);

Cytokines: interleukin-2 (also known as aldesleukin and IL-2, sold underthe tradename Proleukin®), interleukin-11 (also known as oprevelkin,sold under the tradename Neumega®), alpha interferon alfa (also known asIFN-alpha, sold under the tradenames Intron® A, and Roferon-A®);

Leutinizing hormone releasing hormone (LHRH) agonists. Goserelin (soldunder the tradename Zoladex®);

Progesterones: megestrol (also known as megestrol acetate, sold underthe tradename Megace®);

Miscellaneous cytotoxic agents. Arsenic trioxide (sold under thetradename Trisenox®), asparaginase (also known as L-asparaginase,Erwinia L-asparaginase, sold under the tradenames Elspar® andKidrolase®);

A compound of formula (I) can also be used in combination with thefollowing adjunct therapies:

Anti-nausea drugs. NK-1 receptor antagonists. Casopitant (sold under thetradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and

Cytoprotective agents. Amifostine (sold under the tradename Ethyol®),leucovorin (also known as calcium leucovorin, citrovorum factor andfolinic acid).

None of the quotations of references made within the present disclosureis to be understood as an admission that the references cited are priorart that would negatively affect the patentability of the presentinvention.

Processes for Making Compounds of the Invention

The present invention also includes processes for the preparation ofcompounds of the invention. In the reactions described, it can benecessary to protect reactive functional groups, for example hydroxy,amino, imino, thio or carboxy groups, where these are desired in thefinal product, to avoid their unwanted participation in the reactions.Conventional protecting groups can be used in accordance with standardpractice, for example, see T. W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Chemistry”, John Wiley and Sons, 1991.

Compounds of Formula I, shown here where R_(8a) is hydrogen, can beprepared by proceeding as in the following General Reaction Scheme I:

in which R₁, R₅ and R_(8b) are as defined for Formula I in the Summaryof the Invention. A compound of Formula I can be prepared by reacting acompound of formula I (where R₃ has a double bond as shown above) with aa suitable reducing agent (such as H₂, and the like) and a suitablecatalyst (such as Palladium on carbon (Pd/C), or the like), under asuitable pressure (such as about 1 atm to about 5 atm). The reactiontakes place at about 0° C.-50° C. and can take from about 1 to about 24hours to complete.

Compounds of Formula I, shown here where R_(8a) is hydrogen and R₃ has adouble bond, can be prepared by proceeding as in the following GeneralReaction Scheme II:

in which R₁, R₅ and R_(8b) are as defined for Formula I in the Summaryof the Invention and Q is a leaving group such as a halogen or triflate.A compound of Formula I can be prepared by reacting a compound offormula 2 with a compound of formula 3 in the presence of a suitablecatalyst (such as Palladium, or the like), a suitable base (such aspotassium carbonate, and the like), and a suitable acid (such as pivalicacid, or the like). The reaction takes place at about 120° C.-200° C.and can take from about 1 to about 18 hours to complete.

Detailed examples of the synthesis of compounds of Formula I can befound in the Examples, infra.

Additional Processes for Making Compounds of the Invention

A compound of the invention can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase.

Compounds of the formula I can also be modified by appending appropriatefunctionalities to enhance selective biological properties.Modifications of this kind are known in the art and include those thatincrease penetration into a given biological system (e.g. blood,lymphatic system, central nervous system, testis), increasebioavailability, increase solubility to allow parenteral administration(e.g. injection, infusion), alter metabolism and/or alter the rate ofsecretion. Examples of this type of modifications include but are notlimited to esterification, e.g. with polyethylene glycols,derivatisation with pivaloyloxy or fatty acid substituents, conversionto carbamates, hydroxylation of aromatic rings and heteroatomsubstitution in aromatic rings. Wherever compounds of the formula I,and/or N-oxides, tautomers and/or (preferably pharmaceuticallyacceptable) salts thereof are mentioned, this comprises such modifiedformulae, while preferably the molecules of the formula I, theirN-oxides, their tautomers and/or their salts are meant.

Alternatively, the salt forms of the compounds of the invention can beprepared using salts of the starting materials or intermediates. In viewof the close relationship between the novel compounds of the formula Iin free form and those in the form of their salts, including those saltsthat can be used as intermediates, for example in the purification oridentification of the novel compounds, any reference to the compounds ora compound of the formula I hereinbefore and hereinafter is to beunderstood as referring to the compound in free form and/or also to oneor more salts thereof, as appropriate and expedient, as well as to oneor more solvates, e.g. hydrates.

Salts are formed, for example, as acid addition salts, preferably withorganic or inorganic acids, from compounds of formula I with a basicnitrogen atom, especially the pharmaceutically acceptable salts.Suitable inorganic acids are, for example, halogen acids, such ashydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organicacids are, for example, carboxylic, phosphonic, sulfonic or sulfamicacids, for example acetic acid, propionic acid, octanoic acid, decanoicacid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid,succinic acid, malonic acid, adipic acid, pimelic acid, suberic acid,azelaic acid, malic acid, tartaric acid, citric acid, amino acids, suchas glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid,methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylicacid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalicacid, phenylacetic acid, mandelic acid, cinnamic acid, methane- orethane-sulfonic acid, 2-hydroxyethanesulfonic acid,ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-toluenesulfonicacid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2- or3-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid,dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- orN-propyl-sulfamic acid, or other organic protonic acids, such asascorbic acid.

For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. For therapeutic use, only pharmaceutically acceptablesalts or free compounds are employed (where applicable in the form ofpharmaceutical preparations), and these are therefore preferred.

The free acid or free base forms of the compounds of the invention canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the invention in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985; Férriz, J. M. et al., Current PharmaceuticalDesign, 2010, 16, 2033-2052). Examples of prodrug derivatives ofcompounds of the invention can be:

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc.,1999.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. While resolution of enantiomers can be carried outusing covalent diastereomeric derivatives of the compounds of theinvention, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chromatography,or preferably, by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981.

In summary, the compounds of Formula I can be made by a process, whichinvolves:

(a) those of general reaction schemes I and II; and

(b) optionally converting a compound of the invention into apharmaceutically acceptable salt;

(c) optionally converting a salt form of a compound of the invention toa non-salt form;

(d) optionally converting an unoxidized form of a compound of theinvention into a pharmaceutically acceptable N-oxide;

(e) optionally converting an N-oxide form of a compound of the inventionto its unoxidized form;

(f) optionally resolving an individual isomer of a compound of theinvention from a mixture of isomers;

(g) optionally converting a non-derivatized compound of the inventioninto a pharmaceutically acceptable prodrug derivative; and

(h) optionally converting a prodrug derivative of a compound of theinvention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

EXAMPLES

The following examples and intermediates serve to illustrate theinvention without limiting the scope thereof.

Some abbreviations used in the examples are as follows: aq. (aqueous);br (broad); ° C. (degrees Celsius); δ NMR chemical shift in ppmdownfield from tetramethyl-silane; d (doublet); DCE (1,2-dichloroethane;DCM (dichloromethane); DIEA (N,N-diisopropylethylamine); DIBAL-H(diisobutylaluminium hydride); DMA (dimethyl-acetamide); DME(dimethoxyethane); DMF (N,N-dimethylformamide); DMSO(dimethylsulfoxide); Et (ethyl); EtOAc (ethyl acetate); g (gram); h(hour); HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate); HRMS (high-resolution mass spectrometry); i-Pr(isopropyl); L (liter); LAH (lithium aluminium hydride); LC/MS (liquidchromatography-mass spectrometry); M (molarity); m (multiplet); Me(methyl); mg (milligram); MHz (megahertz); min (minute); mL(milliliter); μL (microliter); mmol (millimole); N (normal); NBS(N-bromosuccinimide); n-Bu (normal butyl); n-BuLi (n-butyllithium); NMM(N-methylmorpholine); NMR (nuclear magnetic resonance); Ph (phenyl); pH(−log₁₀H⁺ concentration); ppm (parts per million); q (quartet); s(singlet); sat. (saturated); t (triplet); t-Bu (tert-butyl); Tf(trifluoromethanesulfonyl); TFA (trifluoroacetic acid); Ts(p-toluenesulfonyl); TsOH (p-toluenesulfonic acid); TBS(tert-butyldimethylsilyl); TEA (triethylamine); THF (tetrahydrofuran);and TMS (trimethylsilyl).

All intermediates required for the preparation of compounds of Formula Ican be prepared as described in Scheme 1. Employing intermediates H, K,L, O, P, R, T, U, X and Z provided the synthesis of compounds of FormulaI using the transformations described in Scheme 2. In some occasionsexamples can be converted into additional examples as described in theexperimental section.

Intermediates A 2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene (compound1)

To a 5 mL microwave vial was added a solution of6-methoxybenzo[b]thiophene (400 mg, 2.44 mmol) in anhydrous DMA (3 mL)followed by 1-bromo-4-fluorobenzene (448 mg, 2.56 mmol),chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)(BrettPhos palladacycle 1^(st) generation, 97 mg, 0.12 mmol),trimethylacetic acid (746 mg, 7.31 mmol) and potassium carbonate (1.01g, 7.31 mmol). The microwave vial was sealed, purged with nitrogen andsubjected to microwave irradiation at 150° C. for 2 h. Upon completionthe reaction mixture was diluted with water and extracted with EtOAc.The combined organic layers were then washed with brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. The resulting crudematerial was purified via trituration 2× with heptane and the remainingtriturate (containing some product) was concentrated and purified bycolumn chromatography (SiO₂, 0-30% EtOAc/Heptane) to afford2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene (340 mg, 1.32 mmol, 54%yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ ppm=3.79-3.93 (m, 3H), 7.01 (dd,J=8.59, 2.53 Hz, 1H), 7.24-7.42 (m, 2H), 7.56 (d, J=2.53 Hz, 1H),7.67-7.86 (m, 4H). LC/MS (m/z, MH⁺): 258.8.

2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophene (compound 2)

To a 20 mL microwave vial, 6-methoxybenzo[b]thiophene (1 g, 6.09 mmol),2-bromo-5-fluorotoluene (0.808 mL, 6.39 mmol), BrettPhos palladacycle(1st generation) (0.243 g, 0.304 mmol), trimethylacetic acid (1.866 g,18.27 mmol), and K₂CO₃ (2.52 g, 18.27 mmol) were suspended in DMA (10mL). The reaction was heated for 90 min at 150° C. under microwaveradiation. The reaction mixture was diluted with DCM and water. Theorganic layer was collected (phase separator) and concentrated to affordthe crude product. The crude material was concentrated onto to silicagel and purified by column chromatography (SiO₂, 100% Heptanes) toafford 2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophene (730 mg,2.68 mmol, 44% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δppm=7.69 (d, J=9.09 Hz, 1H), 7.43 (dd, J=6.06, 8.59 Hz, 1H), 7.35 (d,J=2.53 Hz, 1H), 7.14 (s, 1H), 7.00-7.10 (m, 2H), 6.90-7.00 (m, 1H), 3.92(s, 3H), 2.47 (s, 3H).

The following compounds were prepared in an analogous fashion utilizingthe appropriate bromide:

Structure Name Physical Data

6-methoxy-2-(4- (trifluoromethoxy)phenyl)- benzo[b]thiophene (compound3) LC/MS (m/z, MH⁺): 324.8

6-methoxy-2- phenylbenzo[b]thiophene (compound 4) LC/MS (m/z, MH⁺):241.3

6-methoxy-2-(4-methoxy- 3-methylphenyl)- benzo[b]thiophene (compound 5)LC/MS (m/z, MH⁺): 285.3

2-(3-fluoro-4- methoxyphenyl)-6- methoxybenzo[b]thiophene (compound 6)LC/MS (m/z, MH⁺): 289.3

Intermediates B 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene(compound 7)

To a 500 mL round bottom flask containing6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (22 g, 81 mmol) in THF(250 mL) at 0° C. was added NBS (15 g, 84 mmol). The reaction mixturewas stirred at 0° C. for 60 min and then allowed to warm to roomtemperature and stirred for an additional 2 h. Upon completion thereaction mixture was concentrated to 50% volume and quenched with sat.aq. sodium thiosulfate solution. The resulting solution was extractedwith diethyether 3× and the combined organic solvent was dried overanhydrous MgSO₄, filtered and concentrated in vacuo to afford3-bromo-6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene (27.5 g, 79mmol, 97% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm=7.63 (d, J=9.1 Hz, 1H),7.55-7.61 (m, 2H), 7.19 (d, J=2.5 Hz, 1H), 6.96-7.02 (m, 1H), 6.87-6.95(m, 2H), 3.81 (s, 3H), 3.79 (s, 3H).

The following compounds were prepared by bromination from thecorresponding starting materials as described above:

Structure Name Physical Data

3-bromo-6-methoxy-2-(4- (trifluoromethoxy)phenyl) benzo[b]thiophene(compound 8) LC/MS (m/z, M − H): 403.5

3-bromo-6-methoxy-2- phenylbenzo[b]thiophene (compound 9)

3-bromo-2-(4- fluorophenyl)-6- methoxybenzo[b]thiophene (compound 10)LC/MS (m/z, MH⁺): 338.1

3-bromo-6-methoxy-2-(4- methoxy-3- methylphenyebenzo[b] thiophene(compound 11)

3-bromo-2-(3-fluoro-4- methoxyphenyl)-6- methoxybenzo[b]thiophene(compound 12)

3-bromo-7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and3-bromo-5,7-difluoro-6-methoxy-2-(4-methoxphenyl)benzo[b]thiophene(compounds 13 and 14)

To a round bottom flask, an unseparated mixture of7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and5,7-difluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (380 mg,1.318 mmol) was dissolved in THF (10 mL) and the solution was cooled to0° C. To the solution was added NBS (237 mg, 1.331 mmol). The reactionmixture was stirred at 0° C. for 1 h then warmed to room temperature andstirred for an additional 2 h. The reaction mixture was concentrated toafford the crude product. The crude product was diluted with DCM andsat. Na₂S₂O₃ (sodium thiosulfate). The organic layer was collected(phase separator) and concentrated. The reaction mixture was dilutedwith water and DCM. The organic phase was collected (phase separator)and concentrated to afford the crude product. The crude material waspurified by column chromatography (SiO₂, 0-5% Heptanes/EtOAc) to afford3-bromo-7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (211 mg,0.575 mmol, 43.6% yield) and3-bromo-5,7-difluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (125mg, 0.324 mmol, 24.62% yield).3-bromo-7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene: ¹H NMR(400 MHz, CDCl₃) δ ppm=7.56-7.66 (m, 2H), 7.46 (dd, J=1.01, 8.59 Hz,1H), 7.11 (dd, J=7.58, 8.59 Hz, 1H), 6.90-6.97 (m, 2H), 3.92 (s, 3H),3.79 (s, 3H).3-bromo-5,7-difluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene: ¹HNMR (400 MHz, CDCl₃) δ ppm=7.53-7.68 (m, 2H), 7.48 (d, J=8.59 Hz, 1H),7.15-7.27 (m, 1H), 7.07 (dt, J=2.53, 8.59 Hz, 1H), 3.98 (s, 3H), 4.02(s, 3H).

Intermediates C 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene1-oxide (compound 15)

To a solution of 3-bromo-6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene(4 g, 11.45 mmol) in DCM (20.02 mL) at room temperature was addedtrifluoroacetic acid (20.02 mL) dropwise, the reaction went from orangeto dark brown in color. Upon addition the resulting mixture was stirredat room temp for 10 min and then hydrogen peroxide (30% wt. aq) (1.583mL, 16.47 mmol) was added dropwise. After 90 min at room temperature thereaction mixture was quenched with sodium bisulfite (1.714 g, 16.47mmol) (vigorous bubbling was observed) followed by 3.0 mL of water. Theresulting suspension was stirred vigorously for 15 min and thenconcentrated in vacuo to remove DCM and most of the TFA. The residue waspartitioned between DCM (40 mL) and sat. aq. NaHCO₃ solution (40 mL) andseparated. The organic layer was collected (phase separator) andconcentrated in vacuo to afford the crude product, which was purified bycolumn chromatography (SiO₂, 1-40% EtOAc/Heptane) to afford3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (4.6 g,10.08 mmol, 88% yield) as an orange solid. ¹H NMR (400 MHz, CD₃OD) δppm=7.51-7.65 (m, 2H), 7.37-7.51 (m, 2H), 7.08 (dd, J=2.27, 8.34 Hz,1H), 6.79-6.96 (m, 2H), 3.74 (s, 3H), 3.68 (s, 3H).

The following benzo[b]thiophene 1-oxides were prepared in an analogousfashion as described above:

Structure Name Physical Data

3-bromo-6-methoxy-2-(4- (trifluoromethoxy)phenyl) benzo[b]thiophene1-oxide (compound 16) LC/MS (m/z, MH⁺): 422.1

3-bromo-6-methoxy-2- phenylbenzo[b]thiophene 1-oxide (compound 17) LC/MS(m/z, MH⁺): 337.0

3-bromo-2-(4- fluorophenyl)-6- methoxybenzo[b]thiophene 1-oxide(compound 18) LC/MS (m/z, MH⁺): 355.0

3-bromo-6-methoxy-2-(4- methoxy-3- methylphenyl)benzo[b] thiophene1-oxide (compound 19) LC/MS (m/z, MH⁺): 381.1

3-bromo-2-(3-fluoro-4- methoxyphenyl)-6- methoxybenzo[b]thiophene1-oxide (compound 20) LC/MS (m/z, MH⁺): 385.0

3-bromo-7-fluoro-6- methoxy-2-(4- methoxyphenyl)benzo[b] thiophene1-oxide (compound 21) ¹H NMR (400 MHz, CDCl₃) δ ppm = 7.71-7.82 (m, J =8.59 Hz, 2H), 7.35 (d, J = 8.08 Hz, 1H), 7.17 (t, J = 8.08 Hz, 1H),6.97- 7.09 (m, J = 9.09 Hz, 2H), 3.98 (s, 3H), 3.87 (s, 3H)

3-bromo-5,7-difluoro-6- methoxy-2-(4- methoxyphenyl)benzo[b] thiophene1-oxide (compound 22) ¹H NMR (400 MHz, CDCl₃) δ ppm = 7.55-7.72 (m, 2H),7.36-7.43 (m, 1H), 7.21 (t, J = 7.83 Hz, 1H), 7.11 (t, J = 8.59 Hz, 1H),4.01 (s, 3H), 3.98 (s, 3H)

3-bromo-2-(4-fluoro-2- methylphenyl)-6- methoxybenzo[b]thiophene 1-oxide(compound 23) ¹H NMR (400 MHz, CDCl₃) δ ppm = 7.49-7.70 (m, 2H),7.33-7.45 (m, 1H), 7.17 (dd, J = 2.53, 8.59 Hz, 1H), 6.92-7.12 (m, 2H),3.95 (s, 3H), 2.41 (s, 3H)

Intermediates D 7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiopheneand 5,7-difluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene(compounds 24 and 25))

To a 200 mL round bottom flask,6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (4.5 g, 16.7 mmol) wassuspended in THF (60 mL) and the solution was cooled to −78° C. To thecooled solution was added n-BuLi (2.5 M in hexanes, 11.65 mL, 29.1 mmol)dropwise. After 30 min, the reaction mixture was warmed to 0° C. andstirred for an additional 1 h causing the reaction mixture to go intosolution and turn black. The reaction mixture was cooled to −78° C. andN-fluorobenzenesulfonimide (9.19 g, 29.1 mmol) was added causing thereaction mixture to turn a clear orange. After 20 min at −78° C., thereaction mixture was allowed to gradually warm to room temperature over1 h. The reaction was quenched with MeOH and diluted with DCM and 1 NNaOH. The organic phase was collected (phase separator) and concentratedto afford the crude product. The crude material was purified by columnchromatography (SiO₂, 100% Heptane). The fractions were concentrated toa white solid and triturated with cold MeOH. The precipitate wasdiscarded and the filtrate was concentrated to afford7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and5,7-difluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene as anunseparable mixture (1.8 g, ˜35% yield).

Intermediates E 2-bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene1,1-dioxide (compound 26)

To a solution of 2,3-dibromo-6-methoxybenzo[b]thiophene 1,1-dioxide(2.50 g, 7.06 mmol) in THF (100 mL) at room temperature was added4-bromophenol (1.344 g, 7.77 mmol) and Cs₂CO₃ (6.90 g, 21.19 mmol). Thereaction mixture turned green after ˜1 min of stirring. The mixture wasstirred at room temperature for 18 h after which time the reaction wasquenched with water and diluted with DCM. The organic layer wascollected (phase separator) and concentrated to provide2-bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (3.10g, 6.95 mmol, 98% yield) as a white solid which was used without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ ppm=3.83 (s, 3H), 6.92-7.03 (m,3H), 7.25-7.35 (m, 2H), 7.39-7.50 (m, 2H).

Intermediates F 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene1,1-dioxide (compound 27)

Step 1: To a solution of2-bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (3.10g, 6.95 mmol) in MeOH (10 mL) and DMSO (30 mL) was added NaBH₄ (0.789 g,20.85 mmol). The mixture was stirred at room temperature for 3 h afterwhich time the reaction was quenched with water and diluted with DCM.The organic layer was collected (phase separator) and concentrated toprovide 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (2.47g, 6.73 mmol, 97% yield) as an off white solid which was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ ppm=3.85 (s, 3H), 5.38(s, 1H), 7.02-7.08 (m, 3H), 7.22 (d, J=2.53 Hz, 1H), 7.47-7.60 (m, 3H).

3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (compound 28)

Step 2: To a solution of 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene1,1-dioxide (2.47 g, 6.73 mmol) in THF (90 mL) was added DIBAL-H (1.0 Min DCM, 33.6 mL, 33.6 mmol) in one portion. The mixture was heated to75° C. for 2 h after which time the reaction was cooled to roomtemperature and quenched with EtOAc (32.9 mL, 336 mmol). The resultingsolution was stirred for 10 min before carefully adding 75 mL of waterand potassium sodium tartrate (33.100 g, 117 mmol). The mixture wasvigorously stirred for 10 min and diluted with 75 mL EtOAc. The organiclayer was collected, dried with anhydrous MgSO₄ and concentrated invacuo to afford 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (1.9 g,5.67 mmol, 84% yield) as a white solid which was used without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ ppm=3.81 (s, 3H), 6.46 (s, 1H),6.90 (d, J=9.09 Hz, 3H), 7.16-7.22 (m, 1H), 7.31-7.40 (m, 2H), 7.46 (d,J=9.09 Hz, 1H). LC/MS (m/z, MH⁺): 336.8.

Intermediates G

(E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate(compound 29)

To a microwave vial, 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (500mg, 1.49 mmol), methyl acrylate (770 mg, 8.95 mmol), and Pd(PPh₃)₂Cl₂(157 mg, 0.22 mmol) were suspended in DMF (12 mL) and triethylamine(1.039 mL, 7.46 mmol). The reaction was heated for 60 min at 120° C.under microwave irradiation. The reaction mixture was diluted with DCMand water. The organic layer was collected (phase separator) andconcentrated to obtain the crude product. The crude material waspurified by column chromatography (SiO₂, 1-20% EtOAc/Heptane) to afford(E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate(311 mg, 0.91 mmol, 61% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ ppm=1.46 (s, 3H), 3.73 (s, 3H), 6.28 (d, J=16.17 Hz, 1H), 6.59 (s,1H), 6.90 (dd, J=8.59, 2.02 Hz, 1H), 7.00 (d, J=8.59 Hz, 2H), 7.21 (d,J=2.02 Hz, 1H), 7.37-7.48 (m, 3H), 7.59 (d, J=16.17 Hz, 1H). LC/MS (m/z,MH⁺): 341.1.

(E)-tert-butyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)ox)phenyl)acrylate(compound 30)

To a microwave vial, 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (4 g,11.93 mmol), tert-butyl acrylate (10.49 mL, 71.6 mmol), and Pd(PPh₃)₂Cl₂(1.256 g, 1.79 mmol) were suspended in DMF (12 mL) and triethylamine(8.32 mL, 59.7 mmol). The reaction was heated for 60 min at 120° C.under microwave irradiation. The reaction mixture was diluted with DCMand water. The organic layer was collected (phase separator) andconcentrated to obtain the crude product. The crude material waspurified by column chromatography (SiO₂, 1-20% EtOAc/Heptane) to afford(E)-tert-butyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate(3 g, 7.84 mmol, 66% yield) as a white solid. ¹H NMR (CDCl₃) δppm=7.45-7.63 (m, 4H), 7.27-7.33 (m, 1H), 7.03-7.13 (m, 2H), 6.99 (dd,J=8.8, 2.3 Hz, 1H), 6.66 (s, 1H), 6.30 (d, J=16.2 Hz, 1H), 3.90 (s, 3H),1.55 (s, 9H).

Intermediates H (E)-tert-butyl3-(4-((6-methoxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate(compound 31)

To a 5 mL microwave vial, added a solution of (E)-tert-butyl3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (50 mg, 0.13mmol) in anhydrous DMA (1.5 mL), followed by1-bromo-4-(trifluoromethyl)benzene (35.3 mg, 0.16 mmol),1-bromo-4-fluorobenzene (448 mg, 2.56 mmol),chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)(BrettPhos palladacycle 1^(st) generation, 10.4 mg, 0.013 mmol),trimethylacetic acid (40.1 mg, 0.392 mmol) and potassium carbonate (54.2mg, 0.392 mmol). The microwave vial was sealed, purged and back-filledwith nitrogen. The reaction mixture subjected to microwave irradiationfor 2 h at 150° C. Upon completion the reaction was diluted with EtOAc,and washed with water and brine. The combined organic layer was driedover anhydrous MgSO₄, filtered and concentrated in vacuo to give a redbrown residue which was purified by column chromatography (SiO₂, 0-30%EtOAc/heptane) to afford (E)-tert-butyl3-(4-((6-methoxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3yl)oxy)phenyl)acrylate (59.4 mg, 0.11 mmol, 86% yield). ¹H NMR (400 MHz,CD₃OD) δ ppm=1.42-1.61 (m, 9H), 3.77-3.98 (m, 3H), 6.31 (d, J=15.66 Hz,1H), 6.87-7.04 (m, 3H), 7.28 (d, J=9.09 Hz, 1H), 7.46 (d, J=2.53 Hz,1H), 7.47-7.57 (m, 3H), 7.65 (d, J=8.08 Hz, 2H), 7.89 (d, J=8.08 Hz,2H). LC/MS (m/z, MH⁺): 471.40.

(E)-methyl3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate(compound 32)

To a flask containing (E)-methyl3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (800 mg, 2.35mmol) in anhydrous DMA (3.0 mL) was added 1-iodo-2-isopropylbenzene(0.751 mL, 4.70 mmol) followed bychloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)(BrettPhos palladacycle 1^(st) generation, 188 mg, 0.24 mmol),trimethylacetic acid (0.818 mL, 7.05 mmol) and potassium carbonate (974mg, 7.05 mmol). The flask was sealed, purged and back-filled withnitrogen and the resulting mixture was heated to 150° C. for 2 h afterwhich time the reaction was diluted with EtOAc, and washed with waterand brine. The combined organic layer was dried over anhydrous MgSO₄,filtered and concentrated in vacuo to give a red brown residue which waspurified by column chromatography (SiO₂, 0-30% EtOAc/heptane) to afford(E)-methyl3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate(675 mg, 1.48 mmol, 63% yield). LC/MS (m/z, MH⁺): 459.0.

The following intermediates H were prepared in a similar fashion tocompound 31 using the appropriate intermediates G and the correspondingaryl bromide as starting materials:

Structure Name Physical Data

(E)-tert-butyl 3-(4-((6- methoxy-2-(o- tolyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 33) LC/MS (m/z, MH⁺ − C₄H₉): 417.3

(E)-tert-butyl 3-(4-((2-(4- chlorophenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 34) LC/MS (m/z, MH⁺): 494.4

(E)-tert-butyl 3-(4-((2-(3- fluorophenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 35) LC/MS (m/z, MH⁺): 477.6

(E)-tert-butyl 3-(4-((6- methoxy-2-(2- (trifluoromethyl)phenyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylate (compound 36) LC/MS (m/z, MH⁺− C₄H₉): 471.4

(E)-tert-butyl 3-(4-((2-(2- chlorophenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 37) LC/MS (m/z, MH⁺ − C₄H₉): 437.3

(E)-tert-butyl 3-(4-((6- methoxy-2-(2-methyl-4- (trifluoromethyl)phenyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylate (compound 38)

(E)-tert-butyl 3-(4-((2-(2,4- bis(trifluoromethyl) phenyl)-6-methoxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylate (compound 39)

(E)-tert-butyl 3-(4-((2-(2- isopropylphenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 40) LC/MS (m/z, MH⁺ − C₄H₉): 445.0

(E)-tert-butyl 3-(4-((2-(4- fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylate (compound 41) LC/MS(m/z, MH⁺ − C₄H₉): 435.5

(E)-tert-butyl 3-(4-((2-(2,3- dimethylphenyl)-6-methoxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylate (compound 42) LC/MS(m/z, MH⁺ − C₄H₉): 431.3

(E)-tert-butyl 3-(4-((2-(2,5- dimethylphenyl)-6-methoxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylate (compound 43) LC/MS(m/z, MH⁺ − C₄H₉): 431.4

(E)-tert-butyl 3-(4-((2-(3,5- dimethylisoxazol-4-yl)-6-methoxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylate (compound 44) LC/MS(m/z, MH⁺ − C₄H₉): 422.3

(E)-tert-butyl 3-(4-((6- methoxy-2-(3-methoxy-2- methylphenyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylate (compound 45) LC/MS (m/z, MH⁺ −C₄H₉): 448.3

(E)-tert-butyl 3-(4-((2-(4- fluoro-2- (trifluoromethyl)phenyl)-6-methoxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylate (compound 46) LC/MS(m/z, MH⁺ − C₄H₉): 489.3

(E)-tert-butyl 3-(4-((2-(4- (difluoromethyl)phenyl)-6-methoxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylate (compound 47) LC/MS(m/z,MH⁺ − C₄H₉): 526.4

(E)-tert-butyl 3-(4-((2-(2- ethylphenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 48) LC/MS (m/z, MH⁺ − C₄H₉): 431.4

(E)-tert-butyl 3-(4-((2-(2- acetylphenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 49) LC/MS (m/z, MH⁺ − C₄H₉): 445.3

(E)-tert-butyl 3-(4-((2-(2- (tert-butyl)phenyl)-6-methoxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylate (compound 50)

(E)-tert-butyl 3-(4-((6- methoxy-2-(2- nitrophenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 51) LC/MS (m/z, MH⁺ − C₄H₉): 448.3

(E)-tert-butyl 3-(4-((2-(4- (tert-butyl)phenyl)-6-methoxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylate (compound 52) LC/MS(m/z, M − H): 513.6

(E)-tert-butyl 3-(4-((2-(3,5- dimethylphenyl)-6-methoxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylate (compound 53) LC/MS(m/z, MH⁺): 487.5

(E)-tert-butyl 3-(4-((2-(2- isocyanophenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 54) LC/MS (m/z, MH⁺): 484.4

(S,E)-tert-butyl 3-(4-((2-(2- (1-hydroxyethyl)phenyl)-6-methoxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylate (compound 55)

Intermediates K tert-butyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)propanoate(compound 56)

To a solution of (E)-tert-butyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate(27 mg, 0.06 mmol) in 4:1 MeOH:DCM (2.5 mL) was added palladium oncarbon (10% wt., 0.59 mg, 5.53 mol). The reaction was stirred at roomtemperature under a hydrogen balloon for 12 h after which the reactionwas purged with nitrogen and filtered through Celite™. The remainingpalldium was washed with DCM (30 mL) and the resulting solution wasconcentrated in vacuo to afford tert-butyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)propanoate(27 mg, 0.06 mmol, 100% yield) which was used without furtherpurification. LC/MS (m/z, MH⁺): 491.3.

Intermediates L(E)-2-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-1,3,4-oxadiazole(compound 57)

To a 30 mL vial,(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (100 mg, 0.230 mmol) and acetohydrazide (85 mg, 1.151 mmol) weredissolved in POCl₃ (2 mL, 21.46 mmol) and the mixture was heated to 100°C. for 18 h. The reaction mixture was cooled to room temperature pouredinto ice. The solution was quenched with sat. sodium bicarb and dilutedwith DCM. The organic layer was collected (phase separator) andconcentrated to provide the crude material. The crude product waspurified by reverse phase HPLC (acidic condition, 0.1% TFA in 30-100%CH₃CN/H₂O) to afford(E)-2-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-1,3,4-oxadiazole(83 mg, 0.176 mmol, 76% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD)δ ppm=2.38 (s, 3H), 2.57 (s, 3H), 3.90 (s, 3H), 6.81-6.98 (m, 4H),6.98-7.08 (m, 2H), 7.28-7.42 (m, 2H), 7.44-7.58 (m, 4H). LC/MS (m/z,MH⁺): 473.4.

The following intermediates were prepared in a similar fashion tointermediates above using the appropriate starting materials:

Structure Name Physical Data

(E)-2-(4-((2-(4-fluoro-2- methylphenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-propyl- 1,3,4-oxadiazole (compound 58) LC/MS (m/z,MH⁺): 501.0

(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-4H-1,2,4-triazole(compound 59)

To a microwave vial,(E)-2-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-1,3,4-oxadiazole(23 mg, 0.049 mmol) and ammonium trifluoroacetate (128 mg, 0.973 mmol)were suspended in toluene (2 mL). The reaction was heated for 18 h at180° C. under microwave irradiation. The reaction mixture wasconcentrated and the crude product was purified by reverse phase HPLC(neutral condition, 0.1% TFA in 20-100% CH₃CN/H₂O) to afford(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-4H-1,2,4-triazole(15 mg, 0.032 mmol, 65% yield) as a white solid. LC/MS (m/z, MH⁺):472.1.

(E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2(3H)-one(compound 60)

Step 1: To a 30 mL screw cap vial,(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (40 mg, 0.092 mmol) was dissolved in DMF (1 mL). The vial wascharged with hydrazine (5.90 mg, 0.184 mmol), HATU (52.5 mg, 0.138mmol), and DIEA (0.048 mL, 0.276 mmol). The reaction mixture was stirredfor 10 min at room temperature. The reaction was quenched with sat. aq.NH₄Cl and diluted with DCM. The organic phase was collected (phaseseparator) and concentrated by vacuum to afford to crude product. Thecrude material was purified by column chromatography (SiO₂, 1-20%MeOH/DCM) to afford(E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2(3H)-one(38 mg, 0.085 mmol, 92% yield). LC/MS (m/z, MH⁺): 449.1

Step 2: To a 30 mL screw cap vial,(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylohydrazide(38 mg, 0.085 mmol) was dissolved in THF (2 mL). The vial was chargedwith 1,1′-carbonyldiimidazole (16.49 mg, 0.102 mmol) and the reactionwas stirred at room temperature for 1 h. The reaction mixture wasacidified with 6 N HCl which caused a precipitate to form. The mixturewas diluted with DCM to dissolve the precipitate. The organic phase wascollected (phase separator) and concentrated to afford(E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2(3H)-one(31 mg, 0.065 mmol, 77% yield) as an off white solid which was usedwithout further purification. LC/MS (m/z, M-H): 473.0

(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide(compound 61)

To a 30 mL screw cap vial,(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (50 mg, 0.115 mmol) was dissolved in DMF (2 mL). The vial wascharged with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (27.0 mg, 0.230mmol), HATU (65.6 mg, 0.173 mmol), and DIEA (0.060 mL, 0.345 mmol). Thereaction mixture was stirred for 30 min at room temperature. Thereaction was quenched with sat. NH₄Cl and diluted with DCM. The organicphase was collected (phase separator) and concentrated by vacuum toafford to crude product. The crude material was purified by columnchromatography (SiO₂, 1-80% Heptanes/EtOAc) to afford(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide(53 mg, 0.099 mmol, 86% yield). ¹H NMR (400 MHz, CD₃OD) δ ppm=1.48-1.73(m, 3H), 1.73-1.96 (m, 3H), 2.36 (s, 3H), 3.56-3.70 (m, 1H), 3.89 (s,3H), 3.98-4.14 (m, 1H), 4.96 (br. s., 1H), 6.35 (d, J=15.66 Hz, 1H),6.79-6.95 (m, 3H), 6.95-7.07 (m, 2H), 7.26-7.39 (m, 2H), 7.39-7.48 (m,3H), 7.52 (d, J=16.17 Hz, 1H). LC/MS (m/z, MH⁺): 534.1.

Intermediates M3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene1-oxide (compound 62)

To a solution of 4-bromophenol (469 mg, 2.71 mmol) in DMF (3 mL) wasadded sodium hydride (60% suspension in oil, 108 mg, 2.71 mmol), theresulting mixture was allowed to stir for 10 min at room temperature. Tothe solution was added3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (900 mg,2.46 mmol) as a solid. The reaction was heated to 80° C. for 18 h. Uponcompleting the reaction was cooled to room temperature, quenched withwater and diluted with DCM. The organic phase was collected (phaseseparator) and concentrated in vacuo to afford the crude product. Thecrude material was purified by column chromatography (SiO₂, 0-60%EtOAc/Heptane) to afford3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene1-oxide (980 mg, 2.14 mmol, 87% yield) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ ppm=7.70-7.78 (m, 2H), 7.53 (d, J=2.02 Hz,1H), 7.41 (d, J=8.59 Hz, 2H), 6.90-7.06 (m, 6H), 3.91 (s, 3H), 3.83 (s,3H).

The following intermediates were prepared in a similar fashion tointermediates above using the appropriate starting materials:

Structure Name Physical Data

(E)-4-(4-((6-methoxy-2-(4- methoxyphenyl)-1- oxidobenzo[b]thiophen-3-yl)oxy)styryl)-6- (trifluoromethyl)pyrimidin- 2(1H)-one (compound 63) ¹HNMR (400 MHz, CDCl₃) δ ppm = 7.86 (d, J = 16.17 Hz, 1H), 7.72- 7.80 (m,2H), 7.58-7.66 (m, J = 8.59 Hz, 2H), 7.56 (d, J = 2.53 Hz, 1H), 7.13-7.21 (m, J = 9.09 Hz, 2H), 7.05-7.11 (m, 1H), 6.90- 7.01 (m, 3H),6.79-6.90 (m, 2H), 3.92 (s, 3H), 3.83 (s, 3H)

(E)-3-(4-((2-(4-fluoro-2- methylphenyl)-6-methoxy-l-oxidobenzo[b]thiophen- 3- yl)oxy)phenyl)acrylonitrile (compound 64) ¹HNMR (400 MHz, CDCl₃) δ ppm = 7.46 (d, J = 2.53 Hz, 1H), 7.13-7.27 (m,5H), 6.86-6.99 (m, 3H), 6.67-6.85 (m, 2H), 5.64 (d, J = 16.67 Hz, 1H),3.83 (s, 3H), 2.24 (s, 3H)

Intermediates N3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene(compound 65)

A solution of3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene1-oxide (970 mg, 2.12 mmol) in THF (5 mL) was cooled to 0° C. To thecooled solution was added LAH (129 mg, 3.39 mmol) in one portion. Thereaction mixture was stirred at 0° C. for 30 min after which the mixturewas poured into 1 M aq. NaHSO₄ solution and extracted with DCM. Theorganic layer was collected (phase separator) and concentrated in vacuoto afford the crude product which was purified by column chromatography(SiO₂, 0-30% EtOAc/Heptane) to afford3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (850mg, 1.93 mmol, 91% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δppm=3.83 (s, 3H), 3.90 (s, 3H), 6.80-6.99 (m, 5H), 7.22-7.32 (m, 2H),7.32-7.44 (m, 2H), 7.65 (d, J=9.09 Hz, 2H).

The following intermediates were prepared in a similar fashion tointermediates above using the appropriate starting materials:

Structure Name Physical Data

(E)-4-(4-((6-methoxy-2-(4- methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-6- (trifluoromethyl)pyrimidin- 2(1H)-one(compound 66) LC/MS (m/z, MH⁺): 551.4

(E)-3-(4-((2-(4-fluoro-2- methylphenyl)-6- methoxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylonitrile (compound 67) ¹H NMR (400 MHz, CDCl₃) δ ppm= 7.21-7.39 (m, 6H), 6.78-7.01 (m, 5H), 5.68 (d, J = 16.67 Hz, 1H), 3.89(s, 3H), 2.35 (s, 3H)

Intermediates O3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (compound68) Br

HO OH

To a 30 mL vial containing3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (100mg, 0.23 mmol) in DCM (1 mL) was added BBr₃ (1 M in hexanes, 0.680 mL,0.68 mmol) and the reaction mixture was stirred for 1 h at roomtemperature. Upon completion the reaction was quenched with 4 mL MeOHand stirred for 10 min. The mixture was the concentrated in vacuo ontosilica gel and the crude material was purified by column chromatography(SiO₂, 1-100% EtOAc/Heptane) to afford3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (72 mg, 0.17mmol, 77% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δppm=7.47-7.57 (m, 2H), 7.35-7.45 (m, 2H), 7.20 (d, J=2.02 Hz, 1H), 7.16(d, J=8.59 Hz, 1H), 6.73-6.90 (m, 5H).

Intermediates P (E)-tert-butyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-vyl)oxy)phenyl)acrylate(compound 69)

To a solution of3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (79mg, 0.18 mmol) in DMF (1.7 mL) was added triethylamine (0.125 mL, 0.90mmol) followed by tert-butyl acrylate (0.184 mL, 1.25 mmol) andPd(PPh₃)₂Cl₂ (18.9 mg, 0.03 mmol). The mixture was then subjected tomicrowave irradiation for 1 h at 120° C. after which the reaction wasdiluted with water (15 mL) and extracted with EtOAc (4×10 mL). Thecombined organic layers were washed with brine (30 mL), passed through aphase separator to remove water and concentrated in vacuo to give thecrude product as an orange oil which was purified by columnchromatography (SiO₂, 0-50% EtOAc/Heptane) to give (E)-tert-butyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylateas a pale yellow oil (55 mg, 0.11 mmol, 63% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm=1.44 (s, 9H), 3.71 (s, 3H), 3.78 (s, 3H), 6.13 (d, J=15.66Hz, 1H), 6.76-6.83 (m, 3H), 6.86 (m, J=8.59 Hz, 2H), 7.14-7.19 (m, 2H),7.31 (m, J=8.59 Hz, 2H), 7.42 (d, J=16.17 Hz, 1H), 7.54 (d, J=8.59 Hz,2H).

(E)-4-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-imidazole(compound 70)

To a microwave vial,3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (50mg, 0.113 mmol) was dissolved in DMF (2 mL) and triethyl amine (0.474mL, 3.40 mmol). To the solution was added tert-butyl4-vinyl-1H-imidazole-1-carboxylate (66.0 mg, 0.340 mmol) andPd(PPh₃)₂Cl₂ (7.95 mg, 0.011 mmol). The system was flushed with nitrogenand heated at 150° C. for 1 h under microwave radiation. The mixture wascooled to room temperature and diluted with DCM and sat. NH4Cl. Theorganic layer was collected (phase separator) and concentrated ontosilica gel and the material was purified by column chromatography (SiO2,0-30% DCM/MeOH) to afford(E)-4-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-imidazole(41 mg, 0.090 mmol, 80% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD)δ 8.78 (d, J=1.52 Hz, 1H), 7.51-7.62 (m, 2H), 7.46-7.51 (m, 1H), 7.39(d, J=9.09 Hz, 2H), 7.32 (d, J=2.53 Hz, 1H), 7.15 (d, J=9.09 Hz, 1H),7.08 (d, J=16.67 Hz, 1H), 6.76-6.95 (m, 6H), 3.77 (s, 3H), 3.69 (s, 3H).

Intermediates Q (E)-methyl3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)acrylate(compound 71)

To a solution of (E)-methyl 3-(4-hydroxyphenyl)acrylate (190 mg, 1.07mmol) in DMF (5 mL) was added sodium hydride (60% suspension in oil,42.7 mg, 1.07 mmol). The resulting mixture was allowed to stir for 10min at room temperature after which3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (300 mg,0.82 mmol) was added, as a solid. The reaction was heated to 80° C. for18 h and upon completion was cooled to room temperature, quenched withwater and diluted with DCM. The organic phase was collected (phaseseparator) and concentrated in vacuo to afford the crude product whichwas purified by column chromatography (SiO₂, 0-80% EtOAc/Heptane) toafford (E)-methyl3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)acrylate(370 mg, 0.80 mmol, 97% yield) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ ppm=7.75 (d, J=9.09 Hz, 2H), 7.65 (d, J=15.66 Hz, 1H), 7.54 (d,J=2.02 Hz, 1H), 7.43-7.52 (m, J=9.09 Hz, 2H), 7.07-7.16 (m, J=8.59 Hz,2H), 6.98-7.07 (m, 1H), 6.93 (d, J=9.09 Hz, 3H), 6.35 (d, J=16.17 Hz,1H), 3.91 (s, 3H), 3.82 (d, J=1.52 Hz, 6H). LC/MS (m/z, MH⁺): 463.4.

The following intermediates were prepared in a similar fashion tointermediates above using the appropriate starting materials:

Structure Name Physical Data

(E)-methyl 3-(4-((5,7- difluoro-6-methoxy-2-(4- methoxyphenyl)-1-oxidobenzo[b]thiophen-3- yl)oxy)phenyl)acrylate (compound 72) ¹H NMR(400 MHz, CDCl₃) δ ppm = 7.62 (d, J = 16.17 Hz, 1H), 7.40- 7.58 (m, 4H),7.03-7.19 (m, 2H), 6.92-7.03 (m, 2H), 6.83 (d, J = 8.08 Hz, 1H), 6.34(d, J = 16.17 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.80 (s, 3H)

(E) Methyl-3-(4-((6- methoxy-2-(4- methoxyphenyl)-1-oxidobenzo[b]thiophen-3- yl)oxy)phenyl)but-2-enoic acid (compound 73) ¹HNMR (400 MHz, CD₃OD) δ ppm = 7.48- 7.61 (m, 3H), 7.34-7.45 (m, 2H),6.94-7.16 (m, 4H), 6.77-6.89 (m, 2H), 6.00 (d, J = 1.52 Hz, 1H), 3.81(s, 3H), 3.69 (s, 3H), 3.62 (s, 3H), 2.42 (s, 3H)

(E)-methyl 3-(4-((7-fluoro- 6-methoxy-2-(4- methoxyphenyl)-1-oxidobenzo[b]thiophen-3- yl)oxy)phenyl)acrylate (compound 74) LC/MS(m/z, MH⁺): 481.3

(E)-ethyl3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate(compound 75)

To a solution of (E)-ethyl 3-(4-hydroxyphenyl)-2-methylacrylate (92 mg,0.445 mmol) in DMF (2.0 mL) was added sodium hydride (60% suspension inoil, 17.79 mg, 0.445 mmol), the resulting mixture was allowed to stirfor 30 min at room temperature. To the solution was added3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (125 mg,0.342 mmol) as a suspension in DMF (2.0 mL). The reaction was heated to80° C. for 15 h. Upon completion the reaction was cooled to roomtemperature, quenched with water and extracted with EtOAc. The combinedorganic layers were then washed with water, sat. aq. NaHCO3, brine andthen collected (phase separator) and concentrated in vacuo to afford thecrude product. The crude material was purified by column chromatography(SiO₂, 0-70% EtOAc/Heptane) to afford (E)-ethyl3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate(144 mg, 0.294 mmol, 86% yield). LC/MS (m/z, MH⁺): 491.3

(E)-ethyl 3-(4-hydroxy-2-methylphenyl)acrylate (compound 76)

To a microwave vial containing 4-bromo-3-methylphenol (600 mg, 3.21mmol) in anhydrous DMF (3.0 mL) was added ethyl acrylate (996 mg, 9.94mmol), palladium (II) acetate (72.0 mg, 0.321 mmol),tri(o-tolyl)phosphine (146 mg, 0.481 mmol) and triethylamine (1.57 mL,11.23 mmol). The resulting mixture was sealed and subjected to microwaveirridation at 120° C. for 2 h after which time the reaction was dilutedwith EtOAc and filtered through Celite™. The filtrate was then washedwith water, brine and dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the crude product as a brown oil which waspurified by column chromatography (SiO₂, 0-30% EtOAc/Heptane) to afford(E)-ethyl 3-(4-hydroxy-2-methylphenyl)acrylate (289.8 mg, 1.405 mmol,44% yield). LC/MS (m/z, MH⁺): 207.2.

The following intermediates were prepared in a similar fashion tointermediates above using the appropriate starting materials:

Structure Name Physical Data

(E)-ethyl 3-(4-((6-methoxy- 2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3- yl)oxy)-2- methylphenyl)acrylate (compound 77)LC/MS (m/z, MH⁺): 491.3

(E)-ethyl 3-(2-methoxy-4- ((6-methoxy-2-(4- methoxyphenyl)-l-oxidobenzo[b]thiophen-3- yl)oxy)phenyl)acrylate (compound 78) LC/MS(m/z, MH⁺): 507.3

(E)-ethyl 3-(4-((6-methoxy- 2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3- yl)oxy)-3- methylphenyl)acrylate (compound 79)LC/MS (m/z, MH⁺): 491.3

(E)-methyl 3-(4-((6- methoxy-1-oxido-2-(4- (trifluoromethoxy)phenyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylate (compound 80) LC/MS (m/z,MH⁺): 517.3

(E)-methyl 3-(4-((6- methoxy-1-oxido-2- phenylbenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 81) LC/MS (m/z, MH⁺): 433.3

(E)-methyl 3-(4-((2-(4- fluorophenyl)-6-methoxy-1-oxidobenzo[b]thiophen- 3-yl)oxy)phenyl)acrylate (compound 82) LC/MS(m/z, MH⁺): 451.3

(E)-methyl 3-(4-((6- methoxy-2-(4-methoxy-3 methylphenyl)-1-oxidobenzo[b]thiophen-3 yl)oxy)phenyl)acrylate (compound 83) LC/MS (m/z,MH⁺): 477.4

(E)-methyl 3-(4-((2-(3- fluoro-4-methoxyphenyl)- 6-methoxy-l-oxidobenzo[b]thiophen-3- yl)oxy)phenyl)acrylate (compound 84) LC/MS(m/z, MH⁺): 481.4

Intermediates R (E)-methyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate(compound 85)

To a 30 mL vial containing (E)-methyl3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)acrylate(200 mg, 0.43 mmol) was added THF (5 mL), triphenylphosphine (420 mg,1.60 mmol) and TMS-Cl (0.553 mL, 4.32 mmol). The reaction was heated to75° C. for 18 h after which time the mixture was cooled to roomtemperature, quenched with sat. aq. NaHCO₃ and diluted with DCM. Theorganic phase was collected (phase separator) and concentrated in vacuoto afford the crude product which was purified by column chromatography(SiO₂, 0-60% EtOAc/Heptane) to afford (E)-methyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate(110 mg, 0.25 mmol, 57% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃)8 ppm=7.58-7.73 (m, 3H), 7.38-7.50 (m, J=8.59 Hz, 2H), 7.28 (t, J=2.27Hz, 2H), 6.96-7.05 (m, J=8.59 Hz, 2H), 6.85-6.96 (m, 3H), 6.32 (d,J=15.66 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H).

The following intermediates were prepared in a similar fashion tointermediates above using the appropriate starting materials:

Structure Name Physical Data

(E)-methyl 3-(4-((5,7- difluoro-6-methoxy-2-(4- methoxyphenyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylate (compound 86) ¹H NMR (400 MHz, CDCl₃)δ ppm = 7.54 (d, J = 15.66 Hz, 1H), 7.28- 7.46 (m, 4H), 6.95-7.02 (m,1H), 6.80-6.95 (m, 4H), 6.23 (d, J = 15.66 Hz, 1H), 3.86 (s, 3H), 3.80(s, 3H), 3.70 (s, 3H)

(E)-methyl 3-(4-((6- methoxy-2-(4- methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)but- 2-enoate (compound 87) ¹H NMR (400 MHz,CDCl₃) δ ppm = 7.52-7.65 (m, 2H), 7.27-7.38 (m, 2H), 7.13-7.23 (m, 2H),6.84-6.93 (m, 2H), 6.75- 6.84 (m, 3H), 6.01 (d, J = 1.52 Hz, 1H), 3.80(s, 3H), 3.72 (s, 3H), 3.66 (s, 3H), 2.46 (d, J = 1.01 Hz, 3H)

(E)-methyl 3-(4-((7-fluoro- 6-methoxy-2-(4- methoxyphenyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylate (compound 88) ¹H NMR (400 MHz, CDCl₃)δ ppm = 7.40-7.58 (m, 3H), 7.21-7.30 (m, 2H), 6.87-6.95 (m, 1H),6.75-6.87 (m, 3H), 6.66- 6.75 (m, 2H), 6.13 (d, J = 16.17 Hz, 1H), 3.78(s, 3H), 3.61 (s, 3H), 3.63 (s, 3H)

(E)-ethyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate(compound 89)

To a solution of (E)-ethyl3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate(144 mg, 0.294 mmol) in THF (6.0 mL) was added triphenylphosphine (285mg, 1.086 mmol) and TMS-Cl (0.375 mL, 2.94 mmol). The reaction washeated to 75° C. for 7 h after which time the mixture was cooled to roomtemperature, quenched with sat. aq. NaHCO₃ and extracted with EtOAc, thecombined organic layers were collected (phase separator) andconcentrated in vacuo to afford the crude product which was purified bycolumn chromatography (SiO₂, 0-40% EtOAc/Heptane) to afford (E)-ethyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate(107 mg, 0.225 mmol, 77% yield). LC/MS (m/z, MH⁺): 475.3.

The following intermediates were prepared in a similar fashion tointermediates above using the appropriate starting materials:

Structure Name Physical Data

(E)-ethyl 3-(4-((6-methoxy- 2-(4- methoxyphenyl)benzo[b]thiophen-3-yl)oxy)-2- methylphenyl)acrylate (compound 90)

(E)-ethyl 3-(2-methoxy-4- ((6-methoxy-2-(4- methoxyphenyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylate (compound 91) LC/MS (m/z, MH⁺): 491.3

(E)-ethyl 3-(4-((6-methoxy- 2-(4- methoxyphenyl)benzo[b]thiophen-3-yl)oxy)-3- methylphenyl)acrylate (compound 92) LC/MS (m/z,MH⁺): 475.3

(E)-methyl 3-(4-((6- methoxy-2-(4- (trifluoromethoxy)phenyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylate (compound 93) LC/MS (m/z,MH⁺): 501.2

(E)-methyl 3-(4-((6- methoxy-2- phenylbenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 94) LC/MS (m/z, MH⁺): 417.3

(E)-methyl 3-(4-((2-(4- fluorophenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 95)

(E)-methyl 3-(4-((6- methoxy-2-(4-methoxy-3- methylphenyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylate (compound 96)

(E)-methyl 3-(4-((2-(3- fluoro-4-methoxyphenyl)- 6-methoxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylate (compound 97)

Intermediates S(E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (compound 98)

To a 30 mL vial containing (E)-methyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate(110 mg, 0.25 mmol) was added THF (2.00 mL), MeOH (1.00 mL), H₂O (1.00mL) and LiOH (29.5 mg, 1.23 mmol). The resulting mixture was stirred atroom temperature for 60 min after which the reaction was concentrated invacuo, diluted with water, and acidified to pH 2 with 6 M HCl causing aprecipitate to form. The mixture was diluted with 20 mL DCM and 2 mLMeOH and the organic layer was collected (phase separator) andconcentrated in vacuo to afford(E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (98 mg, 0.23 mmol, 92% yield) as a yellow solid. ¹H NMR (400 MHz,CD₃OD) δ ppm=7.51-7.69 (m, 5H), 7.43 (d, J=2.02 Hz, 1H), 7.25 (d, J=9.09Hz, 1H), 6.88-7.02 (m, 5H), 6.37 (d, J=15.66 Hz, 1H), 3.89 (s, 3H), 3.80(s, 3H). LC/MS (m/z, MH⁺): 433.0.

The following intermediates were prepared in a similar fashion tointermediates above using the appropriate starting materials:

Structure Name Physical Data

(E)-3-(4-((2-(4- fluorophenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (compound 99) LC/MS (m/z, MH⁺): 421.2

(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (compound 100)

To a 30 mL screw cap vial, (E)-tert-butyl3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate(100 mg, 0.204 mmol) was dissolved in 4M HCl in dioxane (153 μl, 0.612mmol) and the reaction mixture was stirred for 10 min at roomtemperature. The reaction mixture was concentrated to dryness to afford(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (88 mg, 0.202 mmol, 99% yield). ¹H NMR (400 MHz, CD₃OD) δ ppm=2.25(s, 3H) 3.78 (s, 3H) 6.21 (d, J=15.66 Hz, 1H) 6.68-6.84 (m, 3H)6.84-6.92 (m, 2H) 7.16-7.29 (m, 2H) 7.31-7.41 (m, 3H) 7.46 (d, J=16.17Hz, 1H).

Intermediates T(E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylamide(compound 101)

To a 30 mL vial,(E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (98 mg, 0.23 mmol) was dissolved in DMF (2 mL). The vial wascharged with HATU (129 mg, 0.34 mmol) and DIEA (0.119 mL, 0.68 mmol) andthe mixture was stirred for 10 min. A color change from pale orange to adark orange was observed. To the solution was added NH₄Cl (24.24 mg,0.45 mmol) and the reaction mixture was stirred for 30 min at roomtemperature. The reaction was quenched with sat. aq. NH₄Cl and dilutedwith DCM. The organic phase was collected (phase separator) andconcentrated to afford the crude product. The crude material waspurified by column chromatography (SiO₂, 1-10% MeOH/DCM) to afford(E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylamide(77 mg, 0.18 mmol, 79% yield) as an off white solid. ¹H NMR (400 MHz,CD₃OD) δ ppm=8.00 (s, 4H), 7.59-7.70 (m, 2H), 7.45-7.55 (m, 2H), 7.42(d, J=2.02 Hz, 1H), 7.24 (d, J=8.59 Hz, 1H), 6.84-7.02 (m, 4H), 6.52 (d,J=15.66 Hz, 1H), 3.88 (s, 2H), 3.79 (s, 3H). LC/MS (m/z, MH⁺): 432.3.

(E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-(3,3,3-trifluoropropyl)acrylamide(compound 102)

To a 30 mL vial containing(E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (41 mg, 0.10 mmol) was added DMF (3 mL), followed by3,3,3-trifluoropropan-1-amine (13.94 mg, 0.12 mmol), HATU (54.1 mg, 0.14mmol), and DIEA (0.050 mL, 0.28 mmol). The mixture was stirred at roomtemperature for 30 min after which the reaction was quenched with sat.aq. NH₄Cl and diluted with DCM. The organic phase was collected (phaseseparator) and concentrated in vacuo onto silica gel. The crude materialwas purified by column chromatography (SiO₂, 0-30% EtOAc/heptane) toafford(E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-(3,3,3-trifluoropropyl)acrylamide(38 mg, 0.07 mmol, 72% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD)δ ppm=7.64 (d, J=9.09 Hz, 2H), 7.45-7.56 (m, 3H), 7.42 (d, J=2.02 Hz,1H), 7.25 (d, J=8.59 Hz, 1H), 6.90-7.02 (m, 5H), 6.47 (d, J=15.66 Hz,1H), 3.88 (s, 3H), 3.74-3.85 (m, 3H), 3.54 (t, J=7.07 Hz, 2H), 2.34-2.56(m, 2H). LC/MS (m/z, MH⁺): 528.3.

The following intermediates were prepared in a similar fashion tointermediates above using the appropriate starting materials:

Structure Name Physical Data

(E)-3-(4-((2-(4-fluoro-2- methylphenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)phenyl)-N- ((tetrahydro-2H-pyran-2- yl)oxy)acrylamide (compound103) ¹H NMR(400 MHz, CD₃OD) δ ppm = 1.48- 1.73 (m, 3 H) 1.73-1.96 (m, 3H) 2.36 (s, 3 H) 3.56- 3.70 (m, 1 H) 3.89 (s, 3 H) 3.98-4.14 (m, 1 H)4.96 (br. s., 1 H) 6.35 (d, J = 15.66 Hz, 1 H) 6.79- 6.95 (m, 3 H)6.95-7.07 (m, 2 H) 7.26-7.39 (m, 2 H) 7.39-7.48 (m, 3 H) 7.52 (d, J =16.17 Hz, 1 H)

(E)-3-(4-((2-(4- fluorophenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-(3,3,3- trifluoropropyl)acrylamide (compound 104) ¹HNMR(400 MHz, CD₃OD) δ ppm = 7.74 (dd, J = 5.31, 8.84 Hz, 2H), 7.43-7.55(m, 4H), 7.28 (d, J = 9.09 Hz, 1H), 7.13 (t, J = 8.84 Hz, 2H), 6.91-7.03 (m, 3H), 6.47 (d, J = 15.66 Hz, 1H), 3.89 (s, 3H), 3.54 (t, J =6.82 Hz, 2H), 2.37-2.57 (m, 2H)

(E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylamide(compound 105)

(E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (48 mg, 0.115 mmol) was dissolved in DMF (3.00 mL). The vial wascharged with HATU (65.6 mg, 0.173 mmol), DIEA (0.060 mL, 0.345 mmol),and NH₄Cl (6.16 mg, 0.115 mmol). The reaction mixture was stirred for 10min at room temperature. The reaction was quenched with sat. NH₄Cl anddiluted with DCM. The organic phase was collected (phase separator) andconcentrated by vacuum to afford to crude product. The crude materialwas purified by reverse phase HPLC (neutral condition, 3% 1-propanol in1-100% CH₃CN/H₂O) to afford(E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylamide(41 mg, 0.098 mmol, 85% yield) as a pale orange solid. ¹H NMR (400 MHz,CD₃OD) δ ppm=3.77 (s, 3H) 6.40 (d, J=15.66 Hz, 1H) 6.78-6.90 (m, 3H)6.95-7.06 (m, 2H) 7.16 (d, J=8.59 Hz, 1H) 7.29-7.49 (m, 4H) 7.55-7.69(m, 2H).

Intermediates U(E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)stvryl)-1H-tetrazole(compound 106)

To a microwave vial,(E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylamide(75 mg, 0.174 mmol) and Bu₂SnO (4.33 mg, 0.02 mmol) were suspended inDME (3 mL). The vial was charged with TMSN₃ (0.023 mL, 0.17 mmol) andthe reaction was heated for 60 min at 180° C. under microwaveirradiation. The reaction mixture was filtered to remove solids andconcentrated onto silica gel. The crude material was purified by columnchromatography (SiO₂, 1-20% MeOH/DCM) to afford(E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-tetrazole(66 mg, 0.15 mmol, 83% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD)δ ppm=7.45-7.61 (m, 5H), 7.32 (d, J=2.02 Hz, 1H), 7.15 (d, J=9.09 Hz,1H), 6.98 (d, J=16.67 Hz, 1H), 6.86-6.93 (m, 2H), 6.78-6.86 (m, 3H),3.78 (s, 3H), 3.69 (s, 3H). LC/MS (m/z, MH⁺): 457.4.

(E)-5-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1H-tetrazole(compound 107)

To a microwave vial,(E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylamide(41 mg, 0.098 mmol) and Bu₂SnO (2.433 mg, 9.77 mol) were suspended inDME (3 mL). The vial was charged with TMSN₃ (0.013 mL, 0.098 mmol) andthe reaction was heated for 60 min at 180° C. under microwave radiation.The reaction mixture was filtered to remove solids and concentrated ontosilica gel. The crude material was purified by column chromatography(SiO₂, 1-20% DCM/MeOH) to afford(E)-5-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1H-tetrazole(31 mg, 0.070 mmol, 71.4% yield) as an orange solid. ¹H NMR (400 MHz,CD₃OD) δ ppm=3.78 (s, 3H) 6.80-6.91 (m, 3H) 6.96-7.07 (m, 3H) 7.19 (d,J=8.59 Hz, 1H) 7.34 (d, J=2.53 Hz, 1H) 7.35-7.52 (m, 3H) 7.58-7.74 (m,2H).

(E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1-methyl-1H-tetrazoleand(E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-2-methyl-2H-tetrazole(compounds 108 and 109)

To a 30 mL vial containing(E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-2H-tetrazole(15 mg, 0.03 mmol) in DMF (2 mL) was added with iodomethane (2.260 μL,0.04 mmol) and K₂CO₃ (13.62 mg, 0.10 mmol) and the reaction was stirredat room temperature for 18 h. The reaction was quenched with sat. aq.NH₄Cl (15 mL) and extracted with DCM (25 mL). The organic phase wascollected (phase separator) and concentrated in vacuo to afford thecrude product. The crude product was purified by reverse phase HPLC(neutral condition, 3% 1-propanol in 1-100% CH₃CN/H₂O) to afford(E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1-methyl-1H-tetrazole(8 mg, 0.08 mmol, 52% yield) and(E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-2-methyl-2H-tetrazole(6 mg, 0.01 mmol, 39% yield) both as a white solids.

(E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1-methyl-1H-tetrazole:¹H NMR (400 MHz, CD₃OD) δ ppm=7.48-7.60 (m, 3H), 7.39-7.48 (m, 2H), 7.30(d, J=2.02 Hz, 1H), 7.14 (d, J=9.09 Hz, 1H), 6.95 (d, J=16.67 Hz, 1H),6.77-6.90 (m, 5H), 4.24 (s, 3H), 3.76 (s, 3H), 3.68 (s, 3H). LC/MS (m/z,MH⁺): 471.4.

(E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-2-methyl-2H-tetrazole:¹H NMR (400 MHz, CD₃OD) δ ppm=7.75 (d, J=16.17 Hz, 1H), 7.59-7.70 (m,4H), 7.43 (d, J=2.02 Hz, 1H), 7.27 (d, J=8.59 Hz, 1H), 7.09 (d, J=16.17Hz, 1H), 6.97-7.05 (m, 2H), 6.90-6.97 (m, 3H), 4.14 (s, 3H), 3.89 (s,3H), 3.80 (s, 3H). LC/MS (m/z, MH⁺): 471.4.

The following intermediates were prepared in a similar fashion tointermediates above using the appropriate starting materials:

Structure Name Physical Data

(E)-5-(4-((2-(4- fluorophenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)styryl)-2-methyl- 2H-tetrazole (compound 110) ¹H NMR (400 MHz,CD₃OD) δ ppm = 3.78 (s, 3 H) 4.03 (s, 3 H) 6.81- 6.87 (m, 1 H) 6.87-6.93(m, 2 H) 6.95-7.06 (m, 3 H) 7.18 (d, J = 8.59 Hz, 1 H) 7.35 (d, J = 2.53Hz, 1 H) 7.55 (m, J = 9.09 Hz, 2 H) 7.59-7.69 (m, 3 H)

(E)-5-(4-((2-(4- fluorophenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1-methyl- 1H-tetrazole (compound 111) ¹H NMR(400 MHz,CD₃OD) δ ppm = 3.77 (s, 3 H) 4.24 (s, 3H) 6.81- 6.91 (m, 3 H) 6.97-7.07(m, 3 H) 7.18 (d, J = 9.09 Hz, 1 H) 7.33 (d, J = 2.53 Hz, 1 H) 7.41-7.48(m, 2 H) 7.52 (d, J = 16.67 Hz, 1 H) 7.60-7.69 (m, 2 H)

(E)-5-(4-((2-(4-fluoro-2- methylphenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1H- tetrazole (compound 112) ¹H NMR (400 MHz, CD₃Cl) δppm = 7.71 (d, J = 16.67 Hz, 1H), 7.32- 7.44 (m, 2H), 7.22-7.32 (m, 3H),7.00 (d, J = 16.67 Hz, 1H), 6.72-6.95 (m, 5H), 3.85 (s, 3H), 2.33 (s,3H)

(E)-5-(4-((2-(4-fluoro-2- methylphenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)styryl)-2-methyl- 2H-tetrazole (compound 113) ¹H NMR (400 MHz,CD₃OD) δ ppm = 2.26 (s, 3 H) 3.79 (s, 3 H) 4.02 (s, 3 H) 6.74-6.84 (m, 3H) 6.86-6.92 (m, 2 H) 6.94 (d, J = 16.17 Hz, 1 H) 7.20- 7.29 (m, 2 H)7.35 (d, J = 2.02 Hz, 1 H) 7.47 (d, J = 8.59 Hz, 2 H) 7.60 (d, J = 16.17Hz, 1 H)

(E)-5-(4-((2-(4-fluoro-2- methylphenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1-methyl- 1H-tetrazole (compound 114) ¹H NMR (400 MHz,CD₃OD) δ ppm = 2.26 (s, 3 H) 3.78 (s, 3 H) 4.24 (s, 3 H) 6.72-6.84 (m, 3H) 6.85-6.98 (m, 3 H) 7.18- 7.30 (m, 2 H) 7.31-7.40 (m, 3 H) 7.47 (d, J= 16.67 Hz, 1 H)

(E)-5-(4-((2-(4-fluoro-2- methylphenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)styryl)-2-propyl- 2H-tetrazole (compound 115) LC/MS (m/z, MH⁺):501.4

(E)-5-(4-((2-(4-fluoro-2- methylphenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1-propyl- 1H-tetrazole (compound 116) LC/MS (m/z, MH⁺):501.4

Intermediates V methyl5-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)picolinate(compound 117)

To a solution of methyl 5-hydroxypyridine-2-carboxylate (0.273 g, 1.78mmol) in DMF (6.84 mL) at room temperature was added sodium hydride (60%suspension in oil, 0.043 g, 1.78 mmol) and the resulting mixture wasstirred at room temperature for 30 mins. After 30 min at roomtemperature 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzothiophene 1-oxide(0.5 g, 1.37 mmol) was added and the reaction was heated to 80° C. for18 h. Upon completion the reaction was cooled to room temperature,quenched with water and extracted with DCM. The organic layers werecombined, passed through a phase separator and concentrated in vacuo togive the crude product, which was purified by column chromatography(SiO₂, 0-75% EtOAc/heptane) to afford methyl5-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)picolinate(314 mg, 0.72 mmol, 52% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm=3.73 (s,3H), 3.84 (s, 3H), 3.90-3.92 (m, 3H), 6.79-6.86 (m, 2H), 6.91 (dd,J=8.59, 2.53 Hz, 1H), 7.03 (d, J=8.59 Hz, 1H), 7.30 (dd, J=8.59, 3.03Hz, 1H), 7.48 (d, J=2.53 Hz, 1H), 7.55-7.60 (m, 2H), 7.95 (d, J=8.59 Hz,1H), 8.55 (d, J=2.02 Hz, 1H). LC/MS (m/z, MH⁺): 438.2.

Intermediates W(5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-nyoxy)pyridin-2-yl)methanol(compound 118)

Step 1: To a solution of methyl5-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)picolinate(0.314 g, 0.718 mmol) in THF (5.98 mL) at 0° C. was added LAH (1.0 M inTHF, 2.153 mL, 2.15 mmol) dropwise and the reaction was stirred at 0° C.for 1 h. Upon completion the reaction was quenched with water and sat.aq. potassium sodium tartrate and the resulting mixture was stirred for30 min and then extracted with EtOAc (3×). The organic layers werecombined, passed through a phase separator and concentrated in vacuo toafford crude(5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)methanolwhich was used without further purification. LC/MS (m/z, MH⁺): 394.2.

5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)picolinaldehyde(compound 119)

Step 2: To a solution of(5-((6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)methanol(0.266 g, 0.676 mmol) in DCM (3.38 mL) was added manganese dioxide(1.176 g, 13.52 mmol) and the reaction was stirred at room temperaturefor 48 h. Upon completion the reaction was filtered over Celite™ andconcentrated in vacuo to afford crude5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)picolinaldehydewhich was used without further purification. LC/MS (m/z, MH⁺): 392.2.

Intermediates X (E)-methyl3-(5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate(compound 120)

To a solution of5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)picolinaldehyde(0.265 g, 0.68 mmol) in DCM (3.38 mL) at 0° C. was added methyl2-(triphenylphosphoranylidene)acetate (0.543 g, 1.63 mmol) and thereaction was stirred at room temperature for 18 h. Upon completion themixture was concentrated in vacuo to afford crude material which waspurified by column chromatography (SiO₂, 0-25% EtOAc/heptanes) to afford(E)-methyl3-(5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate(96 mg, 0.22 mmol, 32% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm=3.70-3.75(m, 6H), 3.79-3.83 (m, 3H), 6.70 (d, J=15.66 Hz, 1H), 6.77-6.88 (m, 3H),7.02 (dd, J=8.59, 3.03 Hz, 1H), 7.17 (s, 1H), 7.18-7.22 (m, 2H),7.48-7.59 (m, 3H), 8.42 (d, J=2.53 Hz, 1H). LC/MS (m/z, MH⁺): 448.3.

Intermediates Y (E)-ethyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)amino)phenyl)acrylate(compound 121)

To a large microwave vial (10-20 mL) was added3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (350 mg, 1.00mmol), ethyl 4-aminocinnamate (383 mg, 2.00 mmol) and K₃PO₄ (425 mg,2.00 mmol). 1,4-dioxane (6.0 mL) was then added followed bychloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-t-butyl ether adduct (RuPhos palladacycle, 73.0 mg, 0.10 mmol)and the reaction was subjected to microwave irradiation at 120° C. for 3h. Upon completion the reaction mixture was transferred to round bottomflask with EtOAc and concentrated in vacuo. The resulting material waspartitioned between water and EtOAc and separated, the aqueous layer wasthen further extracted with EtOAc (3×) and the combined organic layerswere passed through a phase separator to remove water and concentratedin vacuo. The crude material was purified by column chromatography(SiO₂, 0-30% EtOAc/heptane) to afford (E)-ethyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)amino)phenyl)acrylate(69.0 mg, 0.15 mmol, 15% yield) as a white solid. LC/MS (m/z, MH⁺):460.3.

Intermediates Z (E)-ethyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylate(compound 122)

To a solution of (E)-ethyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)amino)phenyl)acrylate(69.0 mg, 0.15 mmol) in DMF (6.0 mL) at room temperature was added NaH(60% suspension in oil, 139 mg, 3.48 mmol). After 15 min, methyl iodide(0.272 mL, 4.35 mmol) was added and the resulting solution was allowedto stir at room temperature for 45 min after which time the reaction wasquenched with brine and diluted with water. The resulting solution wasthen extracted with EtOAc (3×) and the combined organic layers werewashed with brine (2×), passed through a phase separator andconcentrated in vacuo to afford the crude product which was purified byreverse phase HPLC (neutral condition, 3% 1-propanol in 1-100%CH₃CN/H₂O) to afford ((E)-ethyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylate(25.5 mg, 0.05 mmol, 36% yield) as a white solid. LC/MS (m/z, MH⁺):474.3.

EXAMPLES

For synthesis of examples 1-55: the following examples have beenprepared from the corresponding intermediates by removing the methylgroup(s) from the phenolic ether(s) and in some cases also removing atert-butyl group from a carboxylic ester functionality in the same step.

General Method A

To a solution of the above described intermediate in DCM (0.02-0.1 M) at0° C. was added BBr₃ (1 M in DCM, 1.5-3 eq per MeO— group) dropwise. Theresulting dark mixture was stirred at 0° C. for 1-3 h after which thereaction was quenched with ice water or sat. aq. NaHCO₃ solution. Themixture was allowed to warm up to room temperature and extracted with 5%MeOH in EtOAc. The combined organic phases were concentrated and thecrude product dissolved in MeOH and purified by RP-HPLC to provide theexample.

General Method B:

To a solution of the above described intermediate in DCM (0.02-0.1 M) at0° C. added BBr₃ (1 M in hexanes, 1.5-3 eq. per MeO— group) dropwise.The resulting dark mixture was stirred at 0° C. for 1-3 h after whichthe reaction was quenched with methanol. The mixture was concentrated toa small volume and purified by RP-HPLC to provide the example.

Example 13-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)propanoicacid

To a solution of tert-butyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)propanoate(27 mg, 0.055 mmol) in DCM (1.7 mL) at 0° C. was added BBr₃ (1.0 M inDCM, 0.220 mL, 0.220 mmol) dropwise (reaction turned brown in color anda solid immediately precipitated from the solution). The resultingmixture was stirred at 0° C. for 1 h after which the reaction wasquenched with ice water (3.0 mL) and allowed to warm to room temperaturewith vigorous stirring. The resulting mixture was concentrated in vacuoand dissolved in MeOH (2 mL) then purified by reverse phase HPLC(neutral condition, 3% 1-propanol in 1-100% CH₃CN/H₂O) to afford3-(4-((6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)propanoicacid (7 mg, 0.02 mmol, 31% yield). LC/MS (m/z, MH⁺): 407.0943.

Example 2(E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid

To a solution of (E)-tert-butyl3-(4-((6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)acrylate(40 mg, 0.08 mmol) in DCM (2.5 mL) at 0° C. was added BBr₃ (1.0 M inDCM, 0.33 mL, 0.33 mmol) dropwise, a solid immediately precipitated fromthe solution. The resulting mixture was stirred at 0° C. for 100 minafter which the reaction was quenched by addition of sat. aq. NaHCO₃ (4mL) solution and a white precipitate was observed. The aqueous layer wasthen extracted with 5% MeOH/EtOAc (4×12 mL) and the combined organiclayers were passed through a phase separator to remove water andconcentrated in vacuo to afford the crude product which was dissolved inMeOH (2 mL) and purified by reverse phase HPLC (neutral condition, 3%1-propanol in 1-100% CH₃CN/H₂O) to afford(E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (17.5 mg, 0.04 mmol, 53% yield). LC/MS (m/z, MH⁺): 405.0790.

Example 3(E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid

To a 2-dram vial containing (E)-tert-butyl3-(4-((6-methoxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3yl)oxy)phenyl)acrylate (59.4 mg, 0.113 mmol) in anhydrous DCM (1.5 mL)at 0° C. was added BBr₃ (1.0 M in DCM, 451 μL, 0.451 mmol) dropwise. Theresulting mixture was stirred at 0° C. for 1 h after which the reactionwas quenched with 3 drops of water, diluted with DCM, and extracted withsat. aq. NaHCO₃ (added a few drops of 2-propanol). The organic layer wasdried over anhydrous MgSO₄, filtered concentrated in vacuo to afford thecrude material which was purified by reverse phase HPLC (neutralcondition, 3% 1-propanol in 10-100% CH₃CN/H₂O) to afford(E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (33.8 mg, 0.074 mmol, 66% yield) as a white solid. ¹H NMR (400 MHz,CD₃OD) δ ppm=6.36 (d, J=16.17 Hz, 1H), 6.78-6.89 (m, 1H), 6.98 (d,J=8.59 Hz, 2H), 7.17-7.30 (m, 2H), 7.51-7.70 (m, 5H), 7.88 (d, J=8.08Hz, 2H). HRMS (m/z, MH⁺): 457.0710.

Example 4(E)-3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid

Example 4 was be prepared from the corresponding methylether/tert-butylester intermediates using method A. Example 4 was also prepared, usingthe following hydrolysis reaction: to a solution of (E)-methyl3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate(25.8 mg, 0.058 mmol) in EtOH (1.5 mL) was added LiOH (2.0 M aqueous,0.290 mL, 0.580 mmol). After 5 h at room temperature the reaction wasacidified to pH 3 by addition of 1.0 N aqeuous HCl and extracted with 5%MeOH/EtOAc, the combined organic layers were passed through a phaseseparator and concentrated in vacuo to afford(E)-3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (24.0 mg, 0.056 mmol, 96% yield). LC/MS (m/z, M-H): 429.0.

The following examples were prepared from the correspondingmethylether/tert-butyl ester intermediates using method A:

TABLE 1 Example Structure Name Physical data  4

(E)-3-(4-((6-hydroxy-2- (2-isopropylphenyl)- benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 1.15 (d, J =6.57 Hz, 6 H), 6.30 (d, J = 16.17 Hz, 1 H), 6.76-6.93 (m, 3 H),7.05-7.16 (m, 1 H), 7.19-7.37 (m, 5 H), 7.40-7.48 (m, 2 H), 7.55 (d, J =15.66 Hz, 1 H) HRMS (m/z, MH⁺): 431.1309  5

(E)-3-(4-((6-hydroxy-2- (o-tolyl)benzo- [b]thiophen-3-yl)oxy)-phenyl)acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 2.35 (s, 3 H), 6.34(d, J = 15.66 Hz, 1 H), 6.76-6.82 (m, 2 H), 6.84 (dd, J = 8.84, 2.27 Hz,1 H), 7.13 (d, J = 8.08 Hz, 1 H), 7.16-7.38 (m, 8 H) HRMS (m/z, MH⁺):403.0995  6

(E)-3-(4-((2-(4- chlorophenyl)-6- hydroxybenzo[b] thiophen-3-yl)oxy)phenyl)- acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 6.35 (d, J= 16.17 Hz, 1 H), 6.77-6.85 (m, 1 H), 6.90-7.00 (m, 2 H), 7.19 (d, J =9.09 Hz, 1 H), 7.22 (d, J = 2.02 Hz, 1 H), 7.29-7.38 (m, 2 H), 7.46-7.55(m, 2 H), 7.58 (d, J = 15.66 Hz, 1 H), 7.62- 7.69 (m, 2 H) LC/MS (m/z,MH⁻): 421.40  7

(E)-3-(4-((2-(3- fluorophenyl)-6- hydroxybenzo[b] thiophen-3-yl)oxy)phenyl)- acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 6.39 (d, J= 16.17 Hz, 1 H), 6.82 (dd, J = 8.84, 2.27 Hz, 1 H), 6.88-6.94 (m, 2 H),6.95- 7.03 (m, 1H), 7.16-7.24 (m, 2 H), 7.29-7.39 (m, 2 H), 7.40-7.53(m, 4 H) LC/MS (m/z, MH⁻): 405.40  8

(E)-3-(4-((6-hydroxy-2- (2-(trifluoromethyl)- phenyl)benzo[b]thiophen-3- yl)oxy)phenyl)- acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm =6.32 (d, J = 15.66 Hz, 1 H), 6.78-6.91 (m, 3 H), 7.16-7.28 (m, 2 H),7.45 (d, J = 9.09 Hz, 2 H), 7.49-7.62 (m, 4 H), 7.70-7.81 (m, 1 H) HRMS(m/z, MH⁺): 457.0702  9

(E)-3-(4-((2-(2- chlorophenyl)-6- hydroxybenzo[b] thiophen-3-yl)oxy)phenyl)- acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 6.31 (d, J= 16.17 Hz, 1 H), 6.84-6.88 (m, 1 H), 6.88-6.92 (m, 2 H), 7.24 (d, J =2.02 Hz, 1 H), 7.25-7.34 (m, 3 H), 7.41-7.49 (m, 4 H), 7.56 (d, J =16.17 Hz, 1 H) HRMS (m/z, MH⁺): 423.0446 10

(E)-3-(4-((6-hydroxy-2- (2-methyl-4- (trifluoromethyl)phenyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz, CD₃OD) δppm = 2.44 (s, 3 H), 6.31 (d, J = 15.66 Hz, 1 H), 6.82-6.91 (m, 3 H),7.26 (d, J = 2.02 Hz, 1 H), 7.29 (d, J = 8.59 Hz, 1 H), 7.39- 7.48 (m, 3H), 7.48-7.59 (m, 3H) HRMS (m/z, MH⁺): 471.0851 11

(E)-3-(4-((2-(2,4- bis(trifluoromethyl) phenyl)-6-hydroxy-benzo[b]thiophen-3- yl)oxy)phenyl)-acrylic acid ¹H NMR (400 MHz, CD₃OD)δ ppm = 6.32 (d, J = 15.66 Hz, 1 H), 6.82-6.91 (m, 3 H), 7.26 (dd, J =5.56, 3.03 Hz, 2 H), 7.42-7.49 (m, 2 H), 7.57 (d, J = 16.17 Hz, 1H),7.75 (d, J = 8.08 Hz, 1 H), 7.89 (d, J = 8.08 Hz, 1 H), 8.02 (s, 1 H)HRMS (m/z, MH⁺): 525.0572 12

(E)-3-(4-((2-(4-fluoro- 2-methylphenyl)-6- hydroxybenzo[b] thiophen-3-yl)oxy)phenyl)- acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 2.35 (s, 3H), 6.32 (d, J = 15.66 Hz, 1 H), 6.81-6.92 (m, 4 H), 6.98 (dd, J = 9.60,2.53 Hz, 1 H), 7.24 (d, J = 2.02 Hz, 1 H), 7.27 (d, J = 8.59 Hz, 1 H),7.31 (dd, J = 8.59, 5.56 Hz, 1 H), 7.42-7.49 (m, 2 H), 7.56 (d, J =16.17 Hz, 1 H) HRMS (m/z, MH⁺): 421.0911 13

(E)-3-(4-((2-(2,3- dimethylphenyl)-6- hydroxybenzo[b] thiophen-3-yl)oxy)phenyl)- acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 2.24 (d, J= 12.63 Hz, 6 H), 6.29 (d, J = 16.17 Hz, 1H), 6.79-6.90 (m, 3 H),6.97-7.05 (m, 1 H), 7.11 (dd, J = 14.40, 7.33 Hz, 2 H), 7.20-7.30 (m, 2H), 7.37-7.46 (m, 2 H), 7.55 (d, J = 15.66 Hz, 1 H) HRMS (m/z, MH⁺):417.1139 14

(E)-3-(4-((2-(2,5- dimethylphenyl)-6- hydroxybenzo[b] thiophen-3-yl)oxy)phenyl)- acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 2.09-2.44(m, 6 H), 6.30 (d, J = 16.17 Hz, 1 H), 6.79-6.89 (m, 3 H), 6.98-7.05 (m,1 H), 7.06-7.14 (m, 2 H), 7.21- 7.27 (m, 2 H), 7.39-7.47 (m, 2H), 7.55(d, J = 15.66 Hz, 1H) HRMS (m/z, MH⁺): 417.1144 15

(E)-3-(4-((2-(3,5- dimethylisoxazol-4-yl)- 6-hydroxybenzo-[b]thiophen-3-yl)oxy)- phenyl)acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm= 2.20-2.27 (m, 3 H), 2.33-2.44 (m, 3 H), 6.34 (d, J = 16.17 Hz, 1 H),6.28-6.41 (m, 1 H), 6.81-6.95 (m, 3 H), 7.25 (d, J = 2.02 Hz, 1 H), 7.31(d, J = 8.59 Hz, 1 H), 7.49 (d, J = 8.59 Hz, 2 H), 7.57 (d, J = 15.66Hz, 1 H) HRMS (m/z, MH⁺): 408.0883 16

(E)-3-(4-((6-hydroxy-2- (3-hydroxy-2-methyl- phenyl)benzo[b] thiophen-3-yl)oxy)phenyl)- acrylic acid HRMS (m/z, MH⁺): 419.0938 17

(E)-3-(4-((2-(4-fluoro- 2-(trifluoromethyl)- phenyl)-6-hydroxy-benzo[b]thiophen-3- yl)oxy)phenyl)acrylic acid HRMS (m/z, MH⁺): 475.063418

(E)-3-(4-((2-(2- ethylphenyl)-6- hydroxybenzo[b] thiophen-3-yl)oxy)phenyl)- acrylic acid HRMS (m/z, MH⁺): 417.1148 19

(E)-3-(4-((2-(2- acetylphenyl)-6- hydroxybenzo[b] thiophen-3-yl)oxy)phenyl)- acrylic acid HRMS (m/z, MH⁺): 431.0948 20

(E)-3-(4-((2-(2-(tert- butyl)phenyl)-6- hydroxybenzo[b] thiophen-3-yl)oxy)phenyl)- acrylic acid HRMS (m/z, MH⁺): 445.1465 21

(E)-3-(4-((6-hydroxy-2- (2-nitrophenyl)- benzo[b]thiophen-3-yl)oxy)phenyl)-acrylic acid HRMS (m/z, MH⁺): 434.0625 22

(E)-3-(4-((2-(4-(tert- butyl)phenyl)-6- hydroxybenzo[b] thiophen-3-yl)oxy)phenyl)- acrylic acid HRMS (m/z, MH⁺): 445.1465 23

(E)-3-(4-((2-(3,5- dimethylphenyl)-6- hydroxybenzo[b] thiophen-3-yl)oxy)phenyl)- acrylic acid HRMS (m/z, MH⁺): 417.1157 24

(E)-3-(4-((6-hydroxy-2- (2-isocyanophenyl)- benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid LC/MS (m/z, MH⁻): 412.4 25

(S,E)-3-(4-((6-hydroxy- 2-(2-(1- hydroxyethyl)phenyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylic acid LC/MS (m/z, M − H): 431.4

Example 26(E)-3-(4-((6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid

Step 1: To a 30 mL vial containing (E)-methyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate(100 mg, 0.22 mmol) in DCM (1 mL) was added BBr₃ (1 M in heptane, 0.224mL, 0.22 mmol) and the reaction was stirred for 1 h at room temperature.The reaction mixture was quenched with 4 mL MeOH and stirred for 10 minat room temperature. The crude material was concentrated onto silica geland purified by column chromatography (SiO₂, 1-100% EtOAc/Heptane) toafford (E)-methyl3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate(11 mg, 0.03 mmol, 12% yield), and a mixture of (E)-methyl3-(4-((2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylateand (E)-methyl3-(4-((6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate(32 mg, 0.07 mmol, 33% yield). LC/MS (m/z, MH⁺): 433.2.

Step 2: To a 30 mL vial containing a mixture of (E)-methyl3-(4-((2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylateand (E)-methyl3-(4-((6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate(32 mg, 0.07 mmol) in THF (3 mL), MeOH (1 mL), and H₂O (2 mL) was addedLiOH (9.14 mg, 0.38 mmol). The reaction mixture was stirred for 60 minat room temperature and then concentrated in vacuo, diluted with water,and acidified to pH 2 with 6 M HCl causing a precipitate to form. Themixture was diluted with 20 mL DCM and 2 mL MeOH. The organic layer wascollected (phase separator) and concentrated in vacuo to afford thecrude product. The sample was purified by supercritical fluidchromatography (CHIRALCEL® OJ-H column, 45% MeOH in CO₂) to afford(E)-3-(4-((6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (17 mg, 0.04 mmol, 53% yield) as a white solid. ¹H NMR (400 MHz,(CD₃)₂SO) δ ppm=7.64 (d, J=8.59 Hz, 2H), 7.55-7.62 (m, 2H), 7.51 (d,J=16.17 Hz, 1H), 7.30 (d, J=2.02 Hz, 1H), 7.13 (d, J=8.59 Hz, 1H),6.90-7.04 (m, 4H), 6.83 (dd, J=2.02, 8.59 Hz, 1H), 6.38 (d, J=16.17 Hz,1H), 3.75 (s, 3H). LC/MS (m/z, M-H): 417.5.

Example 27(E)-3-(4-((2-(4-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid

Step 1: To a microwave vial containing (E)-tert-butyl3-(4-((2-(4-(difluoromethyl)phenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate(50 mg, 0.098 mmol) in N-methyl-2-pyrrolidone (1.0 mL) was addedthiophenol (0.015 mL, 0.147 mmol) followed by K₂CO₃ (14 mg, 0.098 mmol).The resulting mixture was subjected to microwave irradiation for 1 h at200° C. after which time the reaction was quenched with brine andextracted with EtOAc. The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the crudematerial which was purified by column chromatography (SiO₂, 0-30%EtOAc/Heptane) to afford (E)-tert-butyl3-(4-((2-(4-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate(30 mg, 0.061 mmol, 62% yield). LC/MS (m/z, M-H): 493.5

Step 2: To a vial containing (E)-tert-butyl3-(4-((2-(4-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate(30 mg, 0.061 mmol) in THF (1.0 mL) was added HCl (4.0 N in dioxane, 0.4mL, 1.600 mmol). The resulting mixture was stirred at 50° C. for 12 hafter which time the reaction was concentrated in vacuo and purified byreverse phase HPLC (neutral condition, 3% 1-propanol in 10-100%CH₃CN/H₂O) to afford(E)-3-(4-((2-(4-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (21 mg, 0.048 mmol, 79% yield). LC/MS (m/z, M-H): 437.5.

Example 28(E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylicacid

To a solution of (E)-ethyl3-(4-((6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate(107 mg, 0.225 mmol) in DCM (5.0 mL) at 0° C. was added BBr₃ (1.0 M inDCM, 0.902 mL, 0.902 mmol) dropwise. The resulting mixture was stirredat 0° C. for 100 min after which the reaction was quenched by additionof sat. aq. NaHCO₃ (4 mL) and acidified to pH 3 by addition ofconcentrated HCl. The aqueous layer was then extracted with 5%MeOH/EtOAc (4×12 mL) and the combined organic layers were passed througha phase separator to remove water and concentrated in vacuo to affordthe crude product which was dissolved in MeOH and purified by reversephase HPLC (neutral condition, 3% 1-propanol in 1-100% CH₃CN/H₂O) toafford(E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylicacid (32.4 mg, 0.078 mmol, 34% yield). HRMS (m/z, MH⁺): 419.0872.

Example 29(E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylicacid

Step 1: To a solution of (E)-methyl3-(5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate(0.096 g, 0.215 mmol) in DCM (2.145 mL) at room temperature was addedBBr₃ (1.0 M in heptane, 0.858 mL, 0.86 mmol) and the reaction wasstirred at room temperature for 30 min. Upon completion the reaction wasquenched with MeOH (2.0 mL) and stirred for 10 min at room temperaturethen concentrated in vacuo onto silica gel then purified by columnchromatography (SiO₂, 0-20% MeOH/DCM) to afford (E)-methyl3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate.LC/MS (m/z, MH⁺): 420.3.

Step 2: To a solution of (E)-methyl3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate(0.118 g, 0.28 mmol) in THF (2.00 mL) and water (2.00 mL) was addedlithium hydroxide (1.0 M aq., 0.844 mL, 0.84 mmol) and the reaction wasstirred at room temperature for 2 h. Upon completion the reaction wasquenched with water, diluted with DCM and acidified to pH 1 with 1 NHCl. The mixture was extracted with DCM (3×) and the combined organiclayers were passed through a phase separator and concentrated in vacuoto afford the crude product which was purified by reverse phase HPLC(acidic condition, 3% TFA in 10-100% CH₃CN/H₂O) to afford(E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylicacid (14 mg, 0.03 mmol, 9% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ ppm=6.66(d, J=15.66 Hz, 1H), 6.77-6.81 (m, 2H), 6.84 (dd, J=8.59, 2.02 Hz, 1H),7.17 (d, J=8.59 Hz, 1H), 7.22 (dd, J=8.59, 3.03 Hz, 1H), 7.31 (d, J=2.02Hz, 1H), 7.44-7.49 (m, 2H), 7.52 (d, J=15.66 Hz, 1H), 7.64 (d, J=8.59Hz, 1H), 8.45 (d, J=2.53 Hz, 1H). LC/MS (m/z, MH⁺): 406.2.

Example 30(E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylicacid

Step 1: To a solution of (E)-ethyl3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylate(25.5 mg, 0.05 mmol) in DCM (1.5 mL) at 0° C. was added BBr₃ (1.0 M inDCM, 0.215 mL, 0.21 mmol) dropwise. After 4 h at 0° C. the reaction wasquenched with sat. aq. NaHCO₃ and extracted with 5% MeOH/EtOAc, thecombined organic layers were passed through a phase separator andconcentrated in vacuo to afford crude (E)-ethyl3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylatewhich was used without further purification. LC/MS (m/z, MH⁺): 446.5.

Step 2: To a solution of crude (E)-ethyl3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylate(25 mg, 0.06 mmol) in EtOH (1.5 mL) at room temperature was added LiOH(2 N aq., 0.168 mL, 0.34 mmol), the reaction was allowed to stir at roomtemperature for 18 h after which time the reaction was quenched with 1 NHCl (4 mL) and concentrated in vacuo to remove EtOH. The resultingsuspension was extracted with 5% MeOH/EtOAc (3×), dried, andconcentrated in vacuo to give the crude product which was purified byreverse phase HPLC (neutral condition, 3% 1-propanol in 1-100%CH₃CN/H₂O) to afford(E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylicacid (4.98 mg, 0.01 mmol, 21% yield) as a white solid. ¹H NMR (400 MHz,CD₃OD) δ ppm=3.12 (s, 3H), 6.11 (d, 1H, J=15.66 Hz), 6.56 (d, 2H, J=8.59Hz), 6.65 (d, 2H, J=9.09 Hz), 6.69 (dd, 1H, J=8.59, 2.02 Hz), 6.98 (d,1H, J=8.59 Hz), 7.11 (d, 1H, J=2.02 Hz), 7.24 (d, 2H, J=9.09 Hz), 7.30(d, 2H, J=9.09 Hz), 7.48 (d, 1H, J=16.17 Hz). HRMS (m/z, MH⁺): 418.1065.

Example 31(E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-(3,3,3-trifluoropropyl)acrylamide

To a 30 mL vial containing(E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-(3,3,3-trifluoropropyl)acrylamide(38 mg, 0.07 mmol) in DCM (1 mL) was added BBr₃ (1 M in heptane, 0.072mL, 0.07 mmol) and the reaction was stirred at room temperature for 1 h.The reaction was quenched with 4 mL MeOH and stirred for 10 min at roomtemperature after which time the resulting mixture was concentrated to50% volume and the crude product was purified by reverse phase HPLC(acidic condition, 0.1% TFA in 1-100% CH₃CN/H₂O) to afford(E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-(3,3,3-trifluoropropyl)acrylamide(31 mg, 0.06 mmol, 86% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD)δ ppm=7.40-7.63 (m, 5H), 7.21 (d, J=2.02 Hz, 1H), 7.15 (d, J=8.59 Hz,1H), 6.88-6.98 (m, 2H), 6.68-6.87 (m, 3H), 6.45 (d, J=15.66 Hz, 1H),3.54 (t, J=7.07 Hz, 2H), 2.46 (tq, J=6.82, 10.95 Hz, 2H). LC/MS (m/z,MH⁺): 500.4.

Example 32(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-hydroxyacrylamide

To a 30 mL screw cap vial,(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide(53 mg, 0.099 mmol) was dissolved in DCM (1 mL). The vial was chargedwith BBr₃ (1.0 M in hexanes, 0.298 mL, 0.298 mmol) and the reactionmixture was stirred for 1 h at room temperature. The reaction mixturewas quenched with 4 mL MeOH and stirred for 10 min. The mixture wasconcentrated onto silica gel and the crude material was purified byreverse phase HPLC (acidic condition, 0.1% TFA in 30-100% CH₃CN/H₂O) toafford(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-hydroxyacrylamide(16 mg, 0.037 mmol, 37% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD)δ ppm=2.25 (s, 3H,) 6.19 (d, J=16.17 Hz, 1H), 6.66-6.84 (m, 4H), 6.88(dd, J=9.85, 2.78 Hz, 1H), 7.06-7.26 (m, 3H), 7.26-7.45 (m, 3H). LC/MS(m/z, MH⁺): 436.1.

The following examples were prepared using procedures described in theabove examples using appropriate starting materials:

TABLE 2 Example Structure Name Physical data 33

(E)-3-(4-((2-(4- fluorophenyl)-6- hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)- N-(3,3,3-trifluoropropyl)- acrylamide ¹H NMR(400 MHz, CD₃OD) δ ppm = 2.26- 2.45 (m, 2H), 3.42 (t, J = 7.07 Hz, 2 H),6.34 (d, J= 16.17 Hz, 1 H), 6.71 (dd, J= 8.59, 2.02 Hz, 1 H), 6.83 (d, J= 8.59 Hz, 2 H), 6.98 (t, J = 8.59 Hz, 2 H), 7.03-7.22 (m, 2 H),7.31-7.50 (m, 3 H), 7.59 (dd, J = 8.59, 5.56 Hz, 2H). LC/MS (m/z, MH⁺):502.3 34

(E)-ethyl 3-(4-((6- hydroxy-2-(4- hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)-2- methylphenyl)acrylate ¹H NMR (400 MHz, CD₃Cl) δppm = 1.37 (t, J = 7.07 Hz, 3 H), 2.39 (s, 3 H), 4.30 (q, J = 7.07 Hz, 2H), 4.81 (br. s., 2 H), 6.28 (d, J = 16.17 Hz, 1 H), 6.76-6.92 (m, 5 H),7.19-7.34 (m, 2 H), 7.49 (d, J = 8.59 Hz, 1 H), 7.56-7.69 (m, 2 H), 7.93(d, J = 15.66 Hz, 1 H) HRMS (m/z, MH⁺): 447.1278 35

(E)-ethyl 3-(4-((6- hydroxy-2-(4- hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)-3- methylphenyl)acrylate ¹H NMR (400 MHz, CD₃OD) δppm = 1.29 (t, J = 7.07 Hz, 3 H), 2.50 (s, 3 H), 4.21 (q, J = 7.07 Hz, 2H), 6.33 (d, J = 16.17 Hz, 1 H), 6.50 (d, J = 8.08 Hz, 1 H), 6.72-6.77(m, 2 H), 6.79 (dd, J = 8.59, 2.02 Hz, 1 H), 7.09 (d, J = 8.59 Hz, 1 H),7.15-7.23 (m, 2 H), 7.44- 7.52 (m, 3 H), 7.53-7.61 (m, 1 H), 7.57 (d, J= 16.17 Hz, 1 H). HRMS (m/z, MH⁺): 447.1243 36

(E)-methyl 3-(4-((2-(4- fluorophenyl)-6- hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)- acrylate ¹H NMR (400 MHz, CD₃Cl) δ ppm = 3.80 (s, 3H), 6.31 (d, J = 15.66 Hz, 1 H), 6.83 (dd, J = 8.59, 2.02 Hz, 1 H),6.93-7.01 (m, 2H), 7.01- 7.11 (m, 2H), 7.23-7.27 (m, 2H), 7.41-7.48 (m,2 H), 7.55-7.73 (m, 3 H). HRMS (m/z, MH⁺): 421.0891 37

(E)-methyl 3-(4-((5,7- difluoro-6-hydroxy-2- (4-hydroxyphenyl)-benzo[b]thiophen-3- yl)oxy)phenyl)acrylate ¹H NMR (400 MHz, CD₃OD) δ ppm= 7.53 (d, J = 16.17 Hz, 1H), 7.45 (d, J = 9.09 Hz, 2H), 7.31 (dd, J =2.02, 12.63 Hz, 1H), 7.19- 7.24 (m, 1H), 6.76-6.93 (m, 5H), 6.31 (d, J =16.17 Hz, 1H), 3.66 (s, 3H) 38

(E)-3-(4-((5,7-difluoro- 6-hydroxy-2-(4- hydroxyphenyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz, CDCl₃) δ ppm =7.61 (d, J = 15.66 Hz, 1H), 7.34-7.44 (m, 3H), 7.23-7.34 (m, 1H),6.84-6.99 (m, 5H), 6.23 (d, J = 15.66 Hz, 1H) 39

(E)-3-(4-((7-fluoro-6- hydroxy-2-(4- hydroxyphenyl)benzo [b]thiophen-3-yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 7.51 (d, J =16.17 Hz, 1H), 7.38-7.47 (m, 4H), 6.80-6.91 (m, 4H), 6.67 (d, J = 9.09Hz, 2H), 6.26 (d, J = 15.66 Hz, 1H). LC/MS (m/z, MH⁺): 423.4 40

(E)-3-(4-((2-(3-fluoro- 4-hydroxyphenyl)-6- hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 6.36 (d, J= 15.66 Hz, 1 H), 6.80 (dd, J = 8.59, 2.02 Hz, 1 H), 6.84-6.91 (m, 1 H),6.92- 6.99 (m, 2 H), 7.16 (d, J = 8.59 Hz, 1 H), 7.20 (d, J = 2.02 Hz, 1H), 7.29 (ddd, J = 8.59, 2.02, 1.01 Hz, 1 H), 7.39 (dd, J = 12.63, 2.02Hz, 1 H), 7.50-7.56 (m, 2 H), 7.60 (d, J = 15.66 Hz, 1 H). HRMS (m/z,MH⁺): 423.0680 41

(E)-methyl 3-(4-((6- hydroxy-2-(4-hydroxy- 3-methylphenyl)-benzo[b]thiophen-3- yl)oxy)phenyl)acrylate LC/MS (m/z, M − H): 431.4 42

(E)-methyl 3-(4-((6- hydroxy-2-(4- (trifluoromethoxy)phenyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylate LC/MS (m/z, M − H): 485.543

(E)-ethyl 3-(4-((6- hydroxy-2-(4- hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)-2- methoxyphenyl)acrylate LC/MS (m/z, MH⁺): 463.244

(E)-methyl 3-(4-((6- hydroxy-2- phenylbenzo[b]thiophen-3-yl)oxy)phenyl)- acrylate HRMS (m/z, MH⁺): 403.0989

Example 45 (E)-methyl3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate

To a solution of (E)-methyl3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate(30 mg, 0.065 mmol) in DCM (1.5 mL) at 0° C. was added BBr₃ (1.0 M inheptane, 0.196 mL, 0.196 mmol) dropwise. After 1 h at 0° C. the reactionwas quenched with sat. aq. NaHCO₃ and extracted with EtOAc, the combinedorganic layers were passed through a phase separator and concentrated invacuo to afford the crude product which was purified by columnchromatography (SiO₂, 0-30% EtOAc/heptane) to afford (E)-methyl3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate(25.8 mg, 0.058 mmol, 89% yield). LC/MS (m/z, M-H): 443.0.

Example 46(E)-2-(4-fluoro-2-methylphenyl)-3-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol

To a 30 mL screw cap vial,(E)-2-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-1,3,4-oxadiazole(12 mg, 0.025 mmol) was dissolved in DCM (0.5 mL). The vial was chargedwith BBr₃ (1.0 M in hexanes, 0.076 ml, 0.076 mmol) and the reactionmixture was stirred for 1 h at room temperature. The reaction mixturewas quenched with 2 mL MeOH and stirred for 10 min. The mixture wasconcentrated onto silica gel and the crude material was purified byreverse phase HPLC (acidic condition, 0.1% TFA in 30-100% CH₃CN/H₂O) toafford(E)-2-(4-fluoro-2-methylphenyl)-3-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol(3 mg, 6.54 mol, 26% yield) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δppm=2.26 (s, 3H), 2.45 (s, 3H), 6.73-6.86 (m, 5H), 6.88 (dd, J=9.85,2.78 Hz, 1H), 7.08-7.30 (m, 3H), 7.34-7.45 (m, 3H). LC/MS (m/z, MH⁺):459.4.

The following examples were prepared using procedures described in theabove examples using appropriate starting materials:

TABLE 3 Example Structure Name Physical data 47

(E)-2-(4-fluoro-2- methylphenyl)-3-(4-(2- (5-propyl-1,3,4- oxadiazol-2-yl)vinyl)phenoxy)benzo [b]thiophen-6-ol ¹H NMR (400 MHz, CD₃OD) δ ppm =0.91-0.98 (m, 3 H), 1.69-1.81 (m, 2 H), 2.26 (s, 3 H), 2.78 (t, J = 7.3Hz, 2 H), 6.72-6.80 (m, 4H), 6.83 (d, J = 16.2 Hz, 1 H), 6.88 (dd, J =9.6, 2.5 Hz, 1 H), 7.14 (d, J = 2.0 Hz, 1 H), 7.18 (d, J = 8.6 Hz, 1 H),7.22 (dd, J = 8.6, 6.1 Hz, 1 H), 7.35-7.45 (m, 3 H) LC/MS (m/z, MH⁺):487.0

Example 48(E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)styry-1,3,4-oxadiazol-2(3H)-one

To a 30 mL screw cap vial,(E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2(3H)-one(15 mg, 0.032 mmol) was dissolved in DCM (1 mL). The vial was chargedwith BBr₃ (1.0 M in hexanes, 0.095 ml, 0.095 mmol) and the reactionmixture was stirred for 1 h at room temperature. The reaction mixturewas quenched with 4 mL MeOH and stirred for 10 min. The mixture wasconcentrated onto silica gel and the crude material was purified byreverse phase HPLC (acidic condition, 0.1% TFA in 30-100% CH₃CN/H₂O) toafford(E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2(3H)-one(6 mg, 0.013 mmol, 41% yield) as a white solid. LC/MS (m/z, MH⁻): 459.0.

Example 49(E)-2-(4-fluoro-2-methylphenyl)-3-(4-(2-(5-methyl-4H-1,2,4-triazol-3-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol

To a 30 mL screw cap vial,(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-4H-1,2,4-triazole(15 mg, 0.032 mmol) was dissolved in DCM (1 mL). The vial was chargedwith BBr₃ (1.0 M in hexanes, 0.095 ml, 0.095 mmol) and the reactionmixture was stirred for 1 h at room temperature. The reaction mixturewas quenched with 4 mL MeOH and stirred for 10 min. The mixture wasconcentrated to 50% volume and purified by reverse phase HPLC (acidiccondition, 0.1% TFA in 30-100% CH₃CN/H₂O) to afford(E)-2-(4-fluoro-2-methylphenyl)-3-(4-(2-(5-methyl-4H-1,2,4-triazol-3-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol(7 mg, 0.015 mmol, 48% yield) as a pale yellow solid.

¹H NMR (400 MHz, CD₃OD) δ ppm=2.26 (s, 3H), 2.42 (s, 3H), 6.72-6.83 (m,5H), 6.88 (dd, J=10.11, 2.53 Hz, 1H), 7.14 (d, J=2.02 Hz, 1H), 7.16-7.26(m, 2H), 7.29-7.41 (m, 3H). LC/MS (m/z, MH⁺): 458.1.

The following examples were prepared from the corresponding methyl etherintermediates using method B:

TABLE 4 Example Structure Name Physical data 50

(E)-4-(4-((6-hydroxy-2- (4-hydroxyphenyl)- benzo[b]thiophen-3-yl)oxy)styryl)-6- (trifluoromethyl) pyrimidin-2(1H)-one ¹H NMR (400 MHz,CD₃OD) δ ppm = 7.81 (d, J = 16.17 Hz, 1H), 7.53 (d, J = 8.59 Hz, 2H),7.34-7.45 (m, 2H), 7.10 (d, J = 2.02 Hz, 1H), 7.06 (t, J = 4.29 Hz, 2H),6.85-6.95 (m, J = 8.59 Hz, 2H), 6.81 (d, J = 16.17 Hz, 1H), 6.70 (dd, J= 2.27, 8.84 Hz, 1H), 6.60- 6.67 (m, 2H) LC/MS (m/z, MH⁺): 523.4 51

(E)-2-(4-fluoro-2- methylphenyl)-3-(4-(2- (1-methyl-1H-tetrazol-5-yl)vinyl)phenoxy)- benzo[b]thiophen-6-ol ¹H NMR (400 MHz, CD₃OD) δ ppm= 2.26 (s, 3 H) 4.24 (s, 3 H) 6.72-6.82 (m, 4 H) 6.85-6.99 (m, 2 H)7.10-7.27 (m, 3 H) 7.32- 7.41 (m, 2 H) 7.47 (d, J = 16.67 Hz, 1 H) LC/MS(m/z, MH⁺): 459.4 52

(E)-2-(4-fluorophenyl)- 3-(4-(2-(1-methyl-1H- tetrazol-5-yl)vinyl)phenoxy)benzo [b]thiophen-6-ol ¹H NMR (400 MHz, CD₃OD) δ ppm =4.24 (s, 3 H) 6.68-6.76 (m, 1 H) 6.82-6.90 (m, 2 H) 6.91- 7.05 (m, 3 H)7.06-7.20 (m, 2 H) 7.39-7.48 (m, 2 H) 7.52 (d, J = 16.67 Hz, 1 H) 7.57-7.68 (m, 2 H) LC/MS (m/z, MH⁺): 445.2 53

(E)-2-(4-fluoro-2- methylphenyl)-3-(4-(2- (1-propyl-1H-tetrazol-5-yl)vinyl)phenoxy) benzo[b]thiophen-6-ol ¹H NMR (400 MHz, CD₃OD) δ ppm= 7.48 (d, J = 16.7 Hz, 1H), 7.32-7.41 (m, 2H), 7.22 (dd, J = 8.6, 6.1Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 6.93 (d, J= 16.7 Hz, 1H), 6.88 (dd, J = 9.9, 2.8 Hz, 1H), 6.71-6.83 (m, 4H), 4.50(t, J = 6.8 Hz, 2H), 2.26 (s, 3H), 1.93 (sxt, J = 7.2 Hz, 2H), 0.78-0.92(m, 3H). LC/MS (m/z, MH⁺): 487.1

Example 54(E)-2-(4-hydroxyphenyl)-3-(4-(2-(1-methyl-1H-tetrazol-5-yl)vinyl)-phenoxy)benzo[b]thiophen-6-ol

To a 30 mL vial containing(E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1-methyl-1H-tetrazole(12 mg, 0.03 mmol) in DCM (1 mL) was added BBr₃ (1 M in heptane, 0.077mL, 0.08 mmol) and the reaction was stirred for 1 h at room temperature.The reaction mixture was quenched with 4 mL MeOH and stirred for 10 minat room temperature. The reaction mixture was concentrated to 50% volumeand the crude product was purified by reverse phase HPLC (acidiccondition, 0.1% TFA in 1-100% CH₃CN/H₂O) to afford(E)-2-(4-hydroxyphenyl)-3-(4-(2-(1-methyl-1H-tetrazol-5-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol(4 mg, 9.04 mol, 35% yield) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ ppm=7.52 (d, J=16.67 Hz, 1H), 7.38-7.48 (m,4H), 7.09 (d, J=2.02 Hz, 1H), 7.06 (d, J=8.59 Hz, 1H), 6.96 (d, J=16.67Hz, 1H), 6.81-6.90 (m, 2H), 6.61-6.73 (m, 3H), 4.24 (s, 3H). LC/MS (m/z,MH⁺): 443.3.

The following examples were prepared using procedures described in theabove examples using appropriate starting materials:

TABLE 5 Example Structure Name Physical data 55

(E)-2-(4- hydroxyphenyl)-3-(4- (2-(2-methyl-2H- tetrazol-5-yl)vinyl)-phenoxy)benzo[b] thiophen-6-ol ¹H NMR (400 MHz, CD₃OD) δ ppm = 7.64 (d,J = 16.17 Hz, 1 H), 7.51- 7.59 (m, J = 8.59 Hz, 2 H), 7.37-7.47 (m, J =8.59 Hz, 2 H), 7.10 (d, J = 2.02 Hz, 1 H), 7.07 (d, J = 8.59 Hz, 1 H),6.97 (d, J = 16.17 Hz, 1 H), 6.88 (d, J = 8.59 Hz, 2 H), 6.61-6.76 (m, 3H), 4.03 (s, 3H). LC/MS (m/z, MH⁺): 443.3

Examples 56-62 were prepared from the corresponding methyl- or ethylester intermediates via ester hydrolysis using general method C: Thecorresponding methyl- or ethyl ester was dissolved in ethanol (0.05-0.1M), 2M aq. LiOH solution (5-10 eq.) was added and the mixture stirred atrt for 16 h. The solution was acidified with 4N HCl and the precipitateextracted with EtOAc. The organic phase was dried over Na₂SO₄ andconcentrated to yield the product. The following examples were preparedutilizing method C from appropriate starting materials:

TABLE 6 Example Structure Name Physical data 56

(E)-3-(4-((6-hydroxy-2- (4-hydroxyphenyl)- benzo[b]thiophen-3-yl)oxy)-2- methylphenyl) acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm =2.34 (s, 3 H), 6.26 (d, J = 16.17 Hz, 1 H), 6.61-6.90 (m, 5 H),7.08-7.32 (m, 2 H), 7.41- 7.65 (m, 3 H), 7.90 (d, J = 16.17 Hz, 1 H)HRMS (m/z, MH⁻): 417.0779 57

(E)-3-(4-((6-hydroxy-2- (4-hydroxyphenyl)- benzo[b]thiophen-3-yl)oxy)-3- methylphenyl)acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm =2.38-2.63 (m, 3H), 6.30 (d, J = 16.17 Hz, 1H), 6.50 (d, J = 8.59 Hz, 1H), 6.73-6.77 (m, 2 H), 6.79 (dd, J = 8.59, 2.02 Hz, 1 H), 7.09 (d, J =8.59 Hz, 1 H), 7.15-7.24 (m, 2 H), 7.42-7.53 (m, 3 H), 7.57 (d, J =16.17 Hz, 1 H) HRMS (m/z, MH⁻): 417.0782 58

(E)-3-(4-((6-hydroxy-2- (4-hydroxyphenyl)- benzo[b]thiophen-3-yl)oxy)-2- methoxyphenyl)acrylic acid LCMS (m/z, MH⁺): 435.1 59

(E)-3-(4-((6-hydroxy-2- (4-(trifluoromethoxy)- phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)- acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 6.37 (d,J = 15.66 Hz, 1 H), 6.82 (dd, J = 8.59, 2.02 Hz, 1 H), 6.91-7.00 (m, 2H), 7.15- 7.32 (m, 4 H), 7.44-7.59 (m, 3 H), 7.71-7.86 (m, 2 H) HRMS(m/z, MH⁺): 473.0644 60

(E)-3-(4-((6-hydroxy-2- phenylbenzo[b]thiophen- 3-yl)oxy)phenyl)-acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 6.28 (d, J = 16.17 Hz, 1H),6.79 (dd, J = 8.59, 2.02 Hz, 1 H), 6.83-6.93 (m, 2 H), 7.09- 7.30 (m, 5H), 7.38 (d, J = 8.59 Hz, 2 H), 7.54 (d, J = 16.17 Hz, 1 H), 7.59-7.68(m, 2 H) HRMS (m/z, MH⁺): 389.0834 61

(E)-3-(4-((6-hydroxy-2- (4-hydroxy-3- methylphenyl)benzo[b] thiophen-3-yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 2.14 (s, 3H), 6.35 (d, J = 15.66 Hz, 1 H), 6.69 (d, J = 8.59 Hz, 1 H), 6.79 (dd, J= 8.59, 2.53 Hz, 1 H), 6.89-7.00 (m, 2 H), 7.15 (d, J = 8.59 Hz, 1 H),7.18 (d, J = 2.02 Hz, 1 H), 7.33 (dd, J = 8.34, 2.27 Hz, 1 H), 7.39 (d,J = 1.52 Hz, 1 H), 7.49-7.55 (m, 2 H), 7.60 (d, J = 16.17 Hz, 1 H) HRMS(m/z, MH⁺): 419.0915 62

(E)-3-(4-((6-hydroxy-2- (4-hydroxyphenyl)- benzo[b]thiophen-3-yl)oxy)phenyl)but-2- enoic acid ¹H NMR (400 MHz, CD₃OD) δ ppm = 7.42 (d,J = 9.09 Hz, 2H), 7.27-7.34 (m, J = 8.59 Hz, 2H), 7.00- 7.13 (m, 2H),6.75-6.82 (m, J = 9.09 Hz, 2H), 6.61- 6.72 (m, 3H), 6.05 (s, 1H), 2.25(d, J = 1.01 Hz, 3H) LC/MS (m/z, M − H): 417.4

Example 63-71 were prepared from the corresponding acid by formation ofthe amide. General method D: the corresponding acid was dissolved in DMF(0.03-0.1 M), HATU (1.5 eq.) was added and the mixture stirred for 5min. DIEA (5 eq.) and the corresponding amine (3 eq.) were added and themixture stirred at rt for 16 h. The mixture was diluted with water andextracted with EtOAc. The combined organic phase was dried over Na₂SO₄and concentrated to yield the crude which was purified by RP-HPLC. Thefollowing examples were prepared utilizing method D:

TABLE 7 Example Structure Name Physical data 63

(E)-3-(4-((6-hydroxy-2- (4-(trifluoromethyl)- phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N- methylacrylamide ¹H NMR (400 MHz, CD₃OD) δ ppm =2.82 (s, 3 H), 6.43 (d, J = 15.66 Hz, 1 H), 6.82 (dd, J = 8.59, 2.02 Hz,1 H), 6.89-7.02 (m, 2 H), 7.13-7.30 (m, 2 H), 7.37-7.52 (m, 3 H), 7.61(d, J = 8.08 Hz, 2 H), 7.85 (d, J = 8.08 Hz, 2 H) HRMS (m/z, MH⁺):470.1018 64

(E)-3-(4-((6-hydroxy-2- (4-hydroxyphenyl)- benzo[b]thiophen-3-yl)oxy)phenyl)acrylamide ¹H NMR (400 MHz, CD₃OD) δ ppm = 6.48 (d, J =15.66 Hz, 1 H), 6.73-6.76 (m, 1 H), 6.76-6.78 (m, 1 H), 6.80 (dd, J =8.84, 2.27 Hz, 1 H), 6.89- 6.98 (m, 2 H), 7.16 (d, J = 8.59 Hz, 1 H),7.19 (d, J = 2.02 Hz, 1 H), 7.42-7.55 (m, 5H) HRMS (m/z, MH⁺): 404.094465

(E)-3-(4-((6-hydroxy-2- (4- hydroxyphenyl)benzo[b] thiophen-3-yl)oxy)phenyl)-N-(2- hydroxyethyl)acrylamide ¹H NMR (400 MHz, CD₃OD) δppm = 3.41 (t, J = 5.56 Hz, 2 H), 3.65 (t, J = 5.81 Hz, 2 H), 6.47 (d, J= 15.66 Hz, 1 H), 6.71-6.77 (m, 2 H), 6.79 (dd, J = 8.59, 2.02 Hz, 1 H),6.88-6.96 (m, 2H), 7.15 (d, J = 9.09 Hz, 1 H), 7.18 (d, J = 2.02 Hz, 1H), 7.42-7.54 (m, 5 H) HRMS (m/z, MH⁺): 448.1205 66

(E)-3-(4-((6-hydroxy-2- (4- hydroxyphenyl)benzo [b]thiophen-3-yl)oxy)phenyl)-N- methylacrylamide ¹H NMR (400 MHz, (CD₃)₂SO) δ ppm =2.66-2.71 (m, 3H), 6.43 (d, J = 15.66 Hz, 1 H), 6.69-6.86 (m, 3 H),6.90-7.00 (m, 2 H), 7.10 (d, J = 8.59 Hz, 1 H), 7.26 (d, J = 2.02 Hz, 1H), 7.33 (d, J = 15.66 Hz, 1 H), 7.42-7.55 (m, 4 H), 7.75-7.87 (m, 1 H)HRMS (m/z, MH⁺): 418.1102 67

(E)-3-(4-((2-(4- fluorophenyl)-6- hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)-N- methylacrylamide ¹H NMR (400 MHz, CD₃OD) δ ppm =2.82 (s, 3 H), 6.44 (d, J = 16.17 Hz, 1 H), 6.77-6.86 (m, 1 H),6.90-6.97 (m, 2 H), 7.04- 7.13 (m, 2 H), 7.18 (d, J = 8.59 Hz, 1H), 7.22(d, J = 2.02 Hz, 1 H), 7.39-7.52 (m, 3 H), 7.65-7.73 (m, 2 H) HRMS (m/z,MH⁺): 420.1044 68

(E)-3-(4-((6-hydroxy-2- (4-hydroxy-3- methylphenyl)benzo[b] thiophen-3-yl)oxy)phenyl)-N- methylacrylamide ¹H NMR (400 MHz, CD₃OD) δ ppm = 2.13(s, 3 H), 2.82 (s, 3 H), 6.43 (d, J = 15.66 Hz, 1H), 6.69 (d, J = 8.59Hz, 1 H), 6.78 (dd, J = 8.59, 2.02 Hz, 1 H), 6.88- 6.96 (m, 2H), 7.14(d, J = 8.59 Hz, 1 H), 7.18 (d, J = 2.02 Hz, 1 H), 7.33 (dd, J = 8.34,2.27 Hz, 1 H), 7.39 (d, J = 2.02 Hz, 1 H), 7.41-7.51 (m, 3 H) HRMS (m/z,MH⁺): 432.1249 69

(E)-3-(4-((2-(3-fluoro- 4-hydroxyphenyl)-6- hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)-N- methylacrylamide ¹H NMR (400 MHz, CD₃OD) δ ppm =2.82 (s, 3 H), 6.44 (d, J = 16.17 Hz, 1 H), 6.76-6.82 (m, 1 H), 6.87 (t,J = 8.84 Hz, 1 H), 6.90- 6.96 (m, 2 H), 7.15 (d, J = 9.09 Hz, 1 H), 7.19(d, J = 2.02 Hz, 1 H), 7.28 (ddd, J = 8.59, 2.02, 1.01 Hz, 1 H), 7.39(dd, J = 12.63, 2.02 Hz, 1 H), 7.42-7.52 (m, 3 H) HRMS (m/z, MH⁺):436.0997

Example 70(E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-methylacrylamide

To a vial containing(E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (15.9 mg, 0.035 mmol) was added DMF (1.0 mL), followed bymethylamine hydrochloride (7.1 mg, 0.105 mmol), HATU (19.9 mg, 0.052mmol), and DIEA (0.030 mL, 0.174 mmol). The mixture was stirred at roomtemperature for 12 h after which the reaction was quenched with waterand extracted with EtOAc. The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the crudeproduct which was purified by reverse phase HPLC (neutral condition, 3%1-propanol in 1-100% CH₃CN/H₂O) to afford(E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-methylacrylamide(13.8 mg, 0.029 mmol, 84% yield). ¹H NMR (400 MHz, CD₃OD) δ ppm=2.82 (s,3H), 6.43 (d, J=15.66 Hz, 1H), 6.82 (dd, J=8.59, 2.02 Hz, 1H), 6.89-7.02(m, 2H), 7.13-7.30 (m, 2H), 7.37-7.52 (m, 3H), 7.61 (d, J=8.08 Hz, 2H),7.85 (d, J=8.08 Hz, 2H). HRMS (m/z, MH⁺): 470.1018.

Example 71(E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)-N-methylacrylamide

To a solution of(E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylicacid (0.057 g, 0.14 mmol) in DMF (1.406 mL) was added HATU (0.064 g,0.17 mmol), methylamine hydrochloride (10.45 mg, 0.16 mmol) and NMM(0.077 mL, 0.70 mmol). The resulting mixture was stirred at roomtemperature for 48 h after which time the reaction was quenched withsat. aq. NH₄Cl and extracted with EtOAc (3×). The combined organiclayers were passed through a phase separator and concentrated in vacuoto afford the crude product which was purified by reverse phase HPLC(acidic condition, 3% TFA in 10-100% CH₃CN/H₂O) to afford(E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)-N-methylacrylamide(30 mg, 0.05 mmol, 37% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δppm=2.67-2.72 (m, 3H), 6.77-6.90 (m, 4H), 7.14-7.23 (m, 2H), 7.30 (d,J=2.02 Hz, 1H), 7.36 (d, J=15.16 Hz, 1H), 7.44-7.51 (m, 3H), 8.42 (d,J=3.03 Hz, 1H). LC/MS (m/z, MH⁺): 419.3.

Examples 72-74 were prepared from the corresponding bromide(Intermediate O) by Heck reaction. General method E: the bromide(intermediate O) was dissolved in DMF (0.02-0.1 M), triethyl amine (10%of DMF), the corresponding terminal alkene (3 eq.) and Pd(PPh₃)₂Cl₂ (0.1eq.) was added and the system purged with nitrogen. The mixture washeated at 150° C. for 1-3 h under microwave irradiation. The mixture wascooled to room temperature and diluted with DCM and sat. aq. NH₄Cl. Theorganic layer was collected (phase separator), concentrated in vacuo andpurified by reverse phase HPLC.

Example 72(E)-3-(4-(2-(1H-imidazol-4-yl)vinyl)phenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol

To a microwave vial containing3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (20 mg, 0.05mmol) in DMF (2 mL) was added triethyl amine (0.202 mL, 1.45 mmol),tert-butyl 4-vinyl-1H-imidazole-1-carboxylate (28.2 mg, 0.15 mmol) andPd(PPh₃)₂Cl₂ (3.40 mg, 4.84 μmol). The system was flushed with nitrogenand heated at 150° C. for 1 h under microwave irradiation. The mixturewas cooled to room temperature and diluted with DCM and sat. aq. NH₄Cl.The organic layer was collected (phase separator), concentrated in vacuoand purified by reverse phase HPLC (basic condition, 0.1% NH₄OH in1-100% CH₃CN/H₂O) to afford(E)-3-(4-(2-(1H-imidazol-4-yl)vinyl)phenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol(3 mg, 7.03 μmol, 15% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δppm=7.57 (s, 1H), 7.43 (d, J=8.59 Hz, 2H), 7.30 (d, J=8.59 Hz, 2H),6.96-7.14 (m, 3H), 6.74-6.96 (m, 4H), 6.53-6.74 (m, 3H). LC/MS (m/z,MH⁺): 427.3.

Example 73(E)-2-(4-hydroxyphenyl)-3-(4-(2-(1-methyl-1H-imidazol-4-yl)vinyl)phenoxy)-benzo[b]thiophen-6-ol

To a microwave vial,3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (50 mg,0.121 mmol) was dissolved in DMF (2 ml) and triethyl amine (0.506 ml,3.63 mmol). To the solution was added the 4-vinyl-1-methyl imidazole(39.2 mg, 0.363 mmol) and Pd(PPh₃)₂Cl₂ (8.49 mg, 0.012 mmol). The systemwas flushed with nitrogen and heated at 150° C. for 1 h under microwaveradiation. The mixture was cooled to room temperature and diluted withDCM and sat. NH4Cl. The organic layer was collected (phase separator)and purified by reverse phase HPLC (acidic condition, 0.1% TFA in 1-100%CH₃CN/H₂O) to afford(E)-2-(4-hydroxyphenyl)-3-(4-(2-(1-methyl-1H-imidazol-4-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol(31 mg, 0.070 mmol, 58.2% yield) as a white solid. ¹H NMR (400 MHz,CD₃OD) δ ppm=3.82 (s, 3H) 6.57-6.74 (m, 3H) 6.75-6.93 (m, 3H) 6.98-7.14(m, 3H) 7.32-7.54 (m, 5H) 8.73 (s, 1H). LC/MS (m/z, MH⁺): 441.3.

The following examples were prepared utilizing method E:

TABLE 8 Example Structure Name Physical data 74

(E)-2-(4- hydroxyphenyl)-3-(4- (2-(1-propyl-1H- imidazol-4-yl)vinyl)phenoxy)benzo [b]thiophen-6-ol ¹H NMR (400 MHz, CD₃OD) δ ppm =1.01 (t, J = 7.33 Hz, 3 H) 1.88-2.03 (m, 2 H) 4.20 (t, J = 7.33 Hz, 2H)6.71-6.85 (m, 3 H) 6.88-7.01 (m, 3 H) 7.11- 7.28 (m, 3 H) 7.44-7.60 (m,4 H) 7.68 (d, J = 1.01 Hz, 1 H) 8.94 (d, J = 1.52 Hz, 1 H). LC/MS (m/z,MH⁺): 469.4 75

(E)-2-(4-hydroxyphenyl)- 3-(4-(2-(1-propyl-1H- imidazol-5-yl)vinyl)phenoxy)benzo[b] thiophen-6-ol LC/MS (m/z, MH⁺): 469.4 this compound isin table 9 - please remove

The following examples were prepared using procedures described in theabove examples 1-75 using appropriate starting materials:

TABLE 9 Example Structure Name Physical data 76

(E)-3-(4-(2-(5- cyclopropyl-1,3,4- oxadiazol-2- yl)vinyl)phenoxy)-2-(4-fluoro-2- methylphenyl)benzo[b] thiophen-6-ol LC/MS (m/z, MH⁺): 485.0 77

(E)-3-(4-((2-(2- ((dimethylamino)methyl) phenyl)-6-hydroxybenzo[b]thiophen- 3-yl)oxy)phenyl)acrylic acid HRMS (m/z, MH⁺):446.1411

Assays

Compounds of the invention were assessed for their ability to be bothpotent estrogen receptor antagonists and to degrade estrogen receptors.The antagonist and degrading properties of the compounds of theinvention described herein can be evidenced by testing in the ERtranscription and ERα degradation assays, respectively.

ER Transcription Assay (MCF7 Cells)

The ER transcription assay is a reporter assay that is based on theability of ER to induce transcription from a luciferase reporter genecontaining estrogen response elements (EREs) in the promoter/enhancerregion. When the reporter gene is transfected in MCF7 cells (containingendogenous ER), transcription is reflected by the level of luciferaseexpression.

MCF7 cells are maintained in DMEM/F12 (Gibco, catalog number 11330)supplemented with 10% fetal bovine serum (FBS) (Gemini Bio-Products,catalog number 100-106). A day before transfection, cells are split intoa T75 flask at a cell density of 300,000 cells/mL (10 mL total) andallowed to attach overnight in a humidified CO₂ incubator at 37° C.

Next day, prior to transfection, media is switched to DMEM/F12 (Gibco,catalog number 21041) supplemented with 10% charcoal-stripped serum(Gemini Bio-Products, catalog number 100-119). MCF7 cells are then bulktransfected, using Lipofectin (Invitrogen, catalog number 18292) withthe following plasmids: 7x-TK-ERE-Luc3 (ER reporter gene) andpCMV-Renilla (normalization control). Briefly, for each T75 flask, 32.5μL of Lipofectin is added to 617.5 μL of OptiMEM (Gibco #11058) andincubated for 30 min at 37 C. Approximately 20 ug DNA is mixed inOptiMEM (Invitrogen) to a total volume of 650 μL. Following incubation,the OptiMEM-DNA mixture is added to the OptiMEM-Lipofectin mix andincubated for 15 minutes at 37° C. The DNA-Lipofectin mixture is thenadded directly to the T75 flask and the flask is returned to theincubator.

After overnight incubation, compound is added to individual wells of a96-well plate in a 10 μL volume of media at 10× concentration along with17β estradiol whose final concentration is 0.1 nM. Normally, DMSO (usedas a vehicle) is included to achieve a final concentration of 0.1% whenadded to the cells. Transfected cells are trypsinized, resuspended inDMEM/F12/10% charcoal-stripped serum and added to the 96-well plate at25,000 cells/well in 90 μL of media. The plate is then returned to theincubator for 24 hours.

After incubation with compounds for 24 hours, Firefly and Renillaluciferase activities are measured to determine ER transcriptionalactivity. Media is removed from 96-well plates by decanting and blottingon paper towels. Cells are lysed with 40 ul/well of 1× passive lysisbuffer (25 mM Tris Phospate, 2 mM CDTA, 10% Glycerol, 0.5% Triton X-100and 2 mM DTT before use) and allowed incubate at room temperature for 10minutes.

Firefly luciferase activity is measured by adding 30 ul Fireflyluciferase assay buffer (20 mM Tricine, 0.1 mM EDTA, 1.07 mM(MgCO₃)₄Mg(OH)₂.5H₂O, 2.67 mM MgSO₄, 33.3 mM DTT, 270 μM Coenzyme A, 470μM luciferin, 530 μM ATP, reconstituted) per well, followed by measuringlight units using a luminometer (BMG labtech FLUOstar OPTIMA). Onesecond total read time after a one second delay.

Renilla luciferase activity is measured by adding 50 ul Renillaluciferase assay buffer (1.1M NaCl, 2.2 mM Na₂EDTA, 0.22 M KxPO₄ (pH5.1), 0.44 mg/mL BSA, 1.3 mM NaN₃, 1.43 uM coelenterazine, final pHadjusted to 5.0), per well, followed by measuring light units using aluminometer. One second total read time after one second delay. IfFirefly luciferase signal is high, Renilla assay must be done an hourafter the Firefly assay due to incomplete squelching of Firefly signal.

ERα Degradation (MCF7 Cells)

Plate MCF7 cells at 0.3 million cells/mL (100 μl/well) in black,clear-bottom 96-well plates (Greiner, catalog number 655090) in DMEM/F12media (Gibco, catalog number 11330) supplemented with 10%charcoal-stripped serum (Gemini Bio-Products, catalog number 100-119),and incubate them at 37° C., 5% CO₂ for 24-36 hours. Next day, make 10×solution of ligands in DMSO and add the solution to the cells to achievea final concentration of 10 uM. A DMSO control is required for relativecalculations, and fulvestrant is used as a positive control for ERdegradation. The cells are subjected to the in-cell Western assay afterincubating cells with ligand for 18-24 hours.

Media is removed from the plates by decanting, and cells are immediatelyfixed with 100 μl of 3.7% formaldehyde in PBS using a multi-channelpipettor. Add formaldehyde to the sides of the wells to avoid celldisruption. Plates are incubated at room temperature for 20 minuteswithout shaking. The fix solution is then removed and cells arepermeabilized with 100 μL/well of 0.1% Triton X-100 in PBS. The lysateis then blocked by adding 50 uL/well of blocking solution (3% goatserum, 1% BSA, 0.1% cold fish skin gelatin and 0.1% Triton X-100 in PBS,pH 7.4) and allowed to shake at room temperature for 2 hr, oralternatively, at 4° C. overnight.

After blocking, 40 μL/well of the primary antibody against ERα (HC-20)(Santa cruz, catalog number 543) diluted at 1:3000 in blocking bufferdiluted 1:3 with PBS is added to each well, except the negative controlwells (which are used for background subtraction) and the plate issealed and incubated overnight at 4° C. Next day, the primary antibodysolution is removed and the wells are washed three times with 0.1% TWEENin PBS, with each wash lasting 5 minutes. 40 μL/well of secondaryantibody (Biotium CF770 goat anti-rabbit 1:2000, catalog number 20078)and DRAQ5 (DNA stain, 5 mM, Thermo Scientific, catalog number 62251)diluted at 1:10000 in blocking buffer diluted 1:3 with PBS is then addedto all the well, including the negative control wells, and the plate isallowed to incubate on shaker at room temperature for 2 hr. Thesecondary antibody solution is then removed and the plates are washedthree times as described above. The plate is then washed one final timewith PBS alone to minimize auto-fluorescence. The plate is then cleanedand read on LiCor Odyssey imager.

For % response calculations, first divide integrated intensities for 700channel (ER) by integrated intensities for 800 channel (DNAnormalization); 700 (ER)/800 (DNA). This will be referred to as thenormalized value. Then subtract average of negative control wells (noprimary antibody) from all normalized values. This corresponds tonegative subtraction. %response=(Value_(unknown)/Value_(DMSO control))*100.

The data describing the antagonist and degradation properties for theexamples is compiled in table 10. The column titled MCF7 IC₅₀ reportsthe inflection point of the inhibition of transcription in MCF7 cells asdescribed above. Percentage ERα remaining reports the remaining ERαprotein measured at 10 μM concentration of the ligand as describedabove. The column ERα IC₅₀ reports the inflection point of thedegradation in response to the ligand concentration. For example,(E)-3-(4-((6-hydroxy-2-(4-hydroxyphenl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (example 2), inhibits 50% of the ERα induced transcriptions in MCF7cells at a concentration of 0.748 μM and degrades the ERα receptor, at a10 μM concentration, by 59%. Half of the observed receptor degradationoccurs at a concentration of 0.026 μM.

TABLE 10 Ex. MCF7 IC₅₀ (μM) % ERα remaining ERα IC₅₀ (μM) 1 0.457 580.031 2 0.748 41 0.026 3 0.941 18 0.034 4 0.006 13 0.001 5 0.089 200.004 6 3.096 21 0.082 7 0.713 22 0.029 8 0.023 17 0.001 9 0.407 180.006 10 0.207 17 0.005 11 0.053 15 0.001 12 0.078 19 0.004 13 0.151 140.002 14 0.238 15 0.006 15 0.404 20 0.012 16 0.128 26 0.006 17 0.012 240.001 18 0.036 23 0.001 19 0.218 19 0.007 20 0.036 22 0.001 21 0.313 220.015 22 0.853 18 0.032 23 0.748 22 0.030 24 2.576 22 0.033 25 0.179 220.006 26 0.647 18 0.021 27 7.972 21 0.085 28 0.886 33 29 7.750 26 303.400 30 31 0.010 45 0.001 32 0.015 25 33 0.073 32 0.010 34 0.048 420.112 35 0.103 33 36 0.137 28 37 0.041 38 38 0.152 25 0.022 39 0.653 240.070 40 0.424 23 0.022 41 10.000 32 42 43 10.000 41 44 10.000 25 45 460.108 41 0.005 47 0.111 43 48 0.422 44 49 0.041 28 50 0.154 36 0.022 510.061 41 0.011 52 5.977 41 0.223 53 0.320 43 54 0.001 39 0.060 55 0.00333 0.034 56 1.270 27 57 1.030 37 0.121 58 5.020 35 59 1.253 17 0.030 602.306 23 0.026 61 0.327 26 0.018 62 0.316 42 63 0.185 26 0.024 64 0.04048 65 0.055 47 66 0.053 40 0.058 67 0.373 36 0.347 68 0.162 43 0.161 690.041 32 0.009 70 0.269 41 71 0.053 39 0.011 72 0.125 47 0.017 73 0.05832 0.010 74 0.108 41 0.005 75 0.01 42 76 0.016 36 77 0.040 15

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims.

We claim:
 1. A compound of formula I:

in which: n is selected from 0, 1 and 2; m is selected from 0, 1 and 2;X is selected from O and NR₆; wherein R₆ is C₁₋₄alkyl; Y₁ is selectedfrom N and CR₇; wherein R₇ is selected from hydrogen and C₁₋₄alkyl; R₁is hydrogen; R₂ is selected from hydrogen and halo; R₃ is selected from—CH₂CH₂R_(8b) and —CR_(8a)═CR_(8a)R_(8b); wherein each R_(8a) isindependently selected from hydrogen, fluoro and C₁₋₄alkyl; and R_(8b)is selected from —C(O)OR_(9a), —C(O)NR_(9a)R_(9b), —C(O)NHOR_(9a),—C(O)X₂R_(9a) and a 5-6 member heteroaryl selected from:

wherein the dotted line indicates the point of attachment with —CH₂CH₂or —CR_(8a)═CR_(8a) of R₃; wherein X₂ is C₁₋₄alkylene; R_(9a) and R_(9b)are independently selected from hydrogen, C₁₋₄alkyl,hydroxy-substituted-C₁₋₄alkyl and halo-substituted-C₁₋₄alkyl; whereinsaid heteroaryl of R_(8b) is unsubstituted or substituted with a groupselected from C₁₋₄alkyl and C₃₋₈cycloalkyl; R₄ is selected fromhydrogen, C₁₋₄alkyl, halo and C₁₋₃alkoxy; R₅ is selected from C₆₋₁₀aryland a 5-6 member heteroaryl selected from:

wherein the dotted line indicates the point of attachment with thebenzothiophene core; wherein said C₆₋₁₀aryl or heteroaryl of R₅ issubstituted with 1 to 3 R_(5a) groups independently selected fromhydroxy, amino, C₁₋₄alkyl, halo, nitro, cyano,halo-substituted-C₁₋₄alkyl, cyano-substituted-C₁₋₄alkyl,hydroxy-substituted-C₁₋₄alkyl, halo-substituted-C₁₋₄alkoxy, C₁₋₄alkoxy,—SF₅, —NR_(11a)R_(11b), —C(O)R_(11a) and a 4-7 member saturated ringcontaining one other heteroatom or group selected from O, NH, andS(O)₀₋₂; wherein R_(11a) and R_(11b) are independently selected fromhydrogen and C₁₋₄alkyl; or R_(11a) and R_(11b) together with thenitrogen to which they are both attached form a 4 to 7 member saturatedring containing one other heteroatom or group selected from O, NH, andS(O)₀₋₂; wherein said 4-7 member ring of R_(5a) can be unsubstituted orsubstituted with C₁₋₄alkyl; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1 of formula Ia:

in which: n is selected from 0, 1 and 2; m is selected from 0, 1 and 2;Y₁ is selected from N and CR₇; wherein R₇ is selected from hydrogen andC₁₋₄alkyl; R₁ is hydrogen; R₂ is selected from hydrogen and halo; R₃ isselected from —CH₂CH₂R_(8b) and —CR_(8a)═CR_(8a)R_(8b); wherein eachR_(8a) is independently selected from hydrogen and C₁₋₄alkyl; and R_(8b)is selected from —C(O)OR_(9a), —C(O)NR_(9a)R_(9b), —C(O)NHOR_(9a),—C(O)X₂R_(9a), tetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl,5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2-oxo-pyrimidinyl andimidazolyl; wherein X₂ is C₁₋₄alkylene; R_(9a) and R_(9b) areindependently selected from hydrogen, C₁₋₄alkyl,hydroxy-substituted-C₁₋₄alkyl and halo-substituted-C₁₋₄alkyl; whereinsaid tetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl,2-oxo-pyrimidinyl or imidazolyl of R_(8b) is unsubstituted orsubstituted with a group selected from C₁₋₄alkyl and C₃₋₈cycloalkyl; R₄is selected from hydrogen and C₁₋₄alkyl; and each R_(5a) isindependently selected from hydroxy, C₁₋₄alkyl, halo, nitro, cyano,halo-substituted-C₁₋₄alkyl, halo-substituted-C₁₋₄alkoxy,hydroxy-substituted-C₁₋₄alkyl, C₁₋₄alkoxy and —C(O)R_(11a); whereinR_(11a) is selected from hydrogen and C₁₋₄alkyl; or a pharmaceuticallyacceptable salt thereof.
 3. The compound of claim 2 in which R₃ isselected from —CH₂CH₂R_(8b) and —CR_(8a)═CR_(8a)R_(8b); wherein eachR_(8a) is independently selected from hydrogen and C₁₋₄alkyl; and R_(8b)is selected from —C(O)OR_(9a), —C(O)NR_(9a)R_(9b), —C(O)NHOR_(9a) and—C(O)X₂R_(9a); wherein X₂ is C₁₋₄alkylene; R_(9a) and R_(9b) areindependently selected from hydrogen, C₁₋₄alkyl,hydroxy-substituted-C₁₋₄alkyl and halo-substituted-C₁₋₄alkyl.
 4. Thecompound of claim 3 in which R₃ is selected from —CH₂CH₂R_(8b) and—CR_(8a)═CR_(8a)R_(8b); wherein each R_(8a) is independently selectedfrom hydrogen and C₁₋₄alkyl; and R_(8b) is selected from —C(O)OH.
 5. Thecompound of claim 4, or the pharmaceutically acceptable salt thereof,selected from:


6. The compound of claim 3, or the pharmaceutically acceptable saltthereof, selected from:


7. The compound of claim 2 in which: R₃ is selected from —CH₂CH₂R_(8b)and —CR_(8a)═CR_(8a)R_(8b); wherein each R_(8a) is independentlyselected from hydrogen and C₁₋₄alkyl; and R_(8b) is selected fromtetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl,5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2-oxo-pyrimidinyl andimidazolyl; wherein said tetrazolyl, 1,3,4-oxadiazolyl,4H-1,2,4-triazolyl, 2-oxo-pyrimidinyl or imidazolyl of R_(8b) isunsubstituted or substituted with a group selected from C₁₋₄alkyl andC₃₋₈cycloalkyl; wherein said phenyl, pyrrolidinyl or indolizinyl of R₃is unsubstituted or substituted with a group selected from —C(O)OR₁₀;wherein R₁₀ is selected from hydrogen and C₁₋₄alkyl.
 8. The compound ofclaim 7, or the pharmaceutically acceptable salt thereof, selected from:


9. The compound of claim 1 or formula Ib:

in which: n is selected from 0, 1 and 2; m is selected from 0, 1 and 2;Y₁ is selected from N and CR₇; wherein R₇ is selected from hydrogen andC₁₋₄alkyl; R₁ is hydrogen; R₂ is selected from hydrogen and halo; R₃ isselected from —CH₂CH₂R_(8b) and —CR_(8a)═CR_(8a)R_(8b); wherein eachR_(8a) is independently selected from hydrogen and C₁₋₄alkyl; and R_(8b)is selected from —C(O)OR_(9a), —C(O)NR_(9a)R_(9b), —C(O)NHOR_(9a),—C(O)X₂R_(9a), tetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl,5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2-oxo-pyrimidinyl andimidazolyl; wherein X₂ is C₁₋₄alkylene; R_(9a) and R_(9b) areindependently selected from hydrogen, C₁₋₄alkyl,hydroxy-substituted-C₁₋₄alkyl and halo-substituted-C₁₋₄alkyl; whereinsaid tetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl,2-oxo-pyrimidinyl or imidazolyl of R_(8b) is unsubstituted orsubstituted with a group selected from C₁₋₄alkyl and C₃₋₈cycloalkyl; R₄is selected from hydrogen and C₁₋₄alkyl; each R_(5a) is independentlyselected from hydroxy, C₁₋₄alkyl, halo, nitro, cyano,halo-substituted-C₁₋₄alkyl, halo-substituted-C₁₋₄alkoxy,hydroxy-substituted-C₁₋₄alkyl, C₁₋₄alkoxy and —C(O)R_(11a); whereinR_(11a) is selected from hydrogen and C₁₋₄alkyl; and R₆ is C₁₋₄alkyl; ora pharmaceutically acceptable salt thereof.
 10. The compound of claim 9in which R₃ is selected from —CH₂CH₂R_(8b) and —CR_(8a)═CR_(8a)R_(8b);wherein each R_(8a) is independently selected from hydrogen andC₁₋₄alkyl; and R_(8b) is selected from —C(O)OR_(9a), —C(O)NR_(9a)R_(9b),—C(O)NHOR_(9a) and —C(O)X₂R_(9a); wherein X₂ is C₁₋₄alkylene; R_(9a) andR_(9b) are independently selected from hydrogen, C₁₋₄alkyl,hydroxy-substituted-C₁₋₄alkyl and halo-substituted-C₁₋₄alkyl.
 11. Thecompounds of claim 10, or the pharmaceutically acceptable salts thereof,selected from:


12. A pharmaceutical composition comprising a compound of claim 1admixed with at least one pharmaceutically acceptable excipient.
 13. Thepharmaceutical composition of claim 12, wherein the excipient isselected from corn starch, potato starch, tapioca starch, starch paste,pre-gelatinized starch, sugars, gelatin, natural gums, synthetic gums,sodium alginate, alginic acid, tragacanth, guar gum, cellulose, ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethylcellulose, methyl cellulose, hydroxypropyl methylcellulose,microcrystalline cellulose, magnesium aluminum silicate, polyvinylpyrrolidone, talc, calcium carbonate, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, agar-agar, sodium carbonate,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, clays, sodium stearate, calcium stearate, magnesium stearate,stearic acid, mineral oil, light mineral oil, glycerin, sorbitol,mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate,hydrogenated vegetable oil, peanut oil, cottonseed oil, sunflower oil,sesame oil, olive oil, corn oil, soybean oil, zinc stearate, sodiumoleate, ethyl oleate, ethyl laureate, silica, and combinations thereof.14. The pharmaceutical composition of claim 13, further comprising anadditional therapeutic agent.
 15. The pharmaceutical composition ofclaim 14, wherein the additional therapeutic agent is selected from ananticancer compound, an analgesic, an antiemetic, an antidepressant, andan anti-inflammatory agent.
 16. A method to treat cancer, comprisingadministering to a subject in need of such treatment an effective amountof a compound of claim
 1. 17. The method of claim 16, wherein the canceris selected from breast, ovarian, endometrial, prostate, uterine,cervical and lung cancers.
 18. The method of claim 17, furthercomprising administering to the subject an additional therapeutic agent.19. The method of claim 18, wherein the additional therapeutic agentcomprises an anticancer drug, a pain medication, an antiemetic, anantidepressant or an anti-inflammatory agent.